Tricyclic degraders of ikaros and aiolos

ABSTRACT

Tricyclic cereblon binders for the degradation of Ikaros or Aiolos by the ubiquitin proteasome pathway for therapeutic applications are described.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/498,617, filed Oct. 11, 2021, which is a continuation ofInternational Application No. PCT/US2020/027678, filed in the U.S.Receiving Office on Apr. 10, 2020, which claims priority to U.S.Provisional Application 62/833,107, filed on Apr. 12, 2019. The entiretyof each of these applications is incorporated herein for all purposes.

FIELD OF THE INVENTION

The invention provides cereblon binders for the degradation of Ikaros(IKZF1) or Aiolos (IKZF3) by the ubiquitin proteasome pathway fortherapeutic applications as described further herein.

BACKGROUND

Protein degradation is a highly regulated and essential process thatmaintains cellular homeostasis. The selective identification and removalof damaged, misfolded, or excess proteins is achieved via theubiquitin-proteasome pathway (UPP). The UPP is central to the regulationof almost all cellular processes, including antigen processing,apoptosis, biogenesis of organelles, cell cycling, DNA transcription andrepair, differentiation and development, immune response andinflammation, neural and muscular degeneration, morphogenesis of neuralnetworks, modulation of cell surface receptors, ion channels and thesecretory pathway, the response to stress and extracellular modulators,ribosome biogenesis and viral infection.

Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitinligase to a terminal lysine residue marks the protein for proteasomedegradation, where the protein is digested into small peptides andeventually into its constituent amino acids that serve as buildingblocks for new proteins. Defective proteasomal degradation has beenlinked to a variety of clinical disorders including Alzheimer's disease,Parkinson's disease, Huntington's disease, muscular dystrophies,cardiovascular disease, and cancer among others.

The Ikaros (“IKZF”) family is a series of zinc-finger proteintranscription factors that are important for certain physiologicalprocesses, particularly lymphocyte development (see Fan, Y. and Lu, D.“The Ikaros family of zinc-finger proteins” Acta Pharmaceutica Sinica B,2016, 6:513-521). Ikaros (“IKZF1”) was first discovered in 1992 (seeGeorgopoulos, K. et al. “Ikaros, an early lymphoid-specifictranscription factor and a putative mediator for T cell commitment”Science, 1992, 258:802-812), and over the subsequent two decades fouradditional homologs have been identified: Helios (“IKZF2”), Aiolos(“IKZF3”), Eos (“IKZF4”), and Pegasus (“IKZF5”) (see John, L. B., andWard, A. C. The Ikaros gene family: transcriptional regulators ofhematopoiesis and immunity” Mol Immunol, 2011, 48:1272-1278). Eachhomolog gene can produce several protein isoforms through alternativesplicing, theoretically allowing for the generation of a large number ofprotein complexes through different combinations of the varioushomologs. Highly conserved among members of this family is a set of twoCys₂His₂ zinc finger motifs at the C-terminus that mediates proteininteractions among various members of the protein family. Up to fourzinc finger motifs at the N-terminus are present for recognition of DNAsequences; with the number of these N-terminal zinc fingers varying dueto alternative splicing. Isoforms without these N-terminal zinc fingersshow a dominant negative effect on transcriptional activation (seeWinandy, S. et al. “A dominant mutation in the Ikaros gene leads torapid development of leukemia and lymphoma” Cell, 1995, 83:289-299).

The distribution of various members of the Ikaros protein family withinthe body varies significantly. Ikaros, Helios, and Aiolos are mainlypresent in lymphoid cells and their corresponding progenitors, withIkaros additionally also detected in the brain, and Ikaros and Heliosalso detected in erythroid cells. Eos and Pegasus are more widelyspread, and found in skeletal muscle, the liver, the brain, and theheart (see Perdomo, J. et al. “Eos and Pegasus, two members of theIkaros family of proteins with distinct DNA binding activities: J BiolChem, 2000, 275:38347-38354; Schmitt, C. et al. “Aiolos and Ikaros:regulators of lymphocyte development, homeostasis andlymphoproliferation” Apoptosis, 2002, 7:277-284; Yoshida, T. andGeorgopoulos, K. “Ikaros fingers on lymphocyte differentiation” Int JHematol, 2014, 100:220-229).

Ikaros is important for proper lymphocyte development. Deletion of theexons encoding the first three N-terminal zinc fingers leads to micelacking T-cells, B-cells, natural killer (NK) cells, and theirprogenitors. Genetic alterations in Ikaros are correlated with a pooroutcome in the treatment of acute lymphoblastic leukemia (ALL). Ikarosand Aiolos are involved in the proliferation of multiple myeloma cells,suggesting a potential role in malignancy.

The drug thalidomide and its analogs lenalidomide and pomalidomide havegarnered interest as immunomodulators and antineoplastics, especially inmultiple myeloma (see Martiniani, R. et al. “Biological activity oflenalidomide and its underlying therapeutic effects in multiple myeloma”Adv Hematol, 2012, 2012:842945; and Terpos, E. et al. “Pomalidomide: anovel drug to treat relapsed and refractory multiple myeloma”Oncotargets and Therapy, 2013, 6:531). While the exact therapeuticmechanism of action of thalidomide, lenalidomide and pomalidomide isunknown, the compounds are used in the treatment of some cancersincluding multiple myeloma. There are also clinical and preclinicalstudies related to the treatment of renal cell carcinoma, glioblastoma,prostate cancer, melanoma, colorectal cancer, crohns disease, rheumatoidarthritis, Bechet's syndrome, breast cancer, head and neck cancer,ovarian cancer, chronic heart failure, graft-versus-host disease, andtuberculous meningitis.

Thalidomide and its analogues have been found to bind to the ubiquitinligase cereblon and redirect its ubiquitination activity (see Ito, T. etal. “Identification of a primary target of thalidomide teratogenicity”Science, 2010, 327:1345). Cereblon forms part of an E3 ubiquitin ligasecomplex which interacts with damaged DNA binding protein 1, forming anE3 ubiquitin ligase complex with Cullin 4 and the E2-binding proteinROC1 (known as RBX1) where it functions as a substrate receptor toselect proteins for ubiquitination.

The binding of lenalidomide to cereblon facilitates subsequent bindingof cereblon to Ikaros and Aiolos, leading to their ubiquitination anddegradation by the proteasome (see Lu, G. et al. “The myeloma druglenalidomide promotes the cereblon-dependent destruction of Ikarosproteins” Science, 2014, 343:305-309; Kronke, J. et al. “Lenalidomidecauses selective degradation of IKZF1 and IKZF3 in multiple myelomacells” Science, 2014, 343:301-305).

The disclosure that thalidomide binds to the cereblon E3 ubiquitinligase led to research to investigate incorporating thalidomide andcertain derivatives into compounds for the targeted destruction ofproteins. Celgene has disclosed imids for similar uses, including thosein U.S. Pat. Nos. 6,045,501; 6,315,720; 6,395,754; 6,561,976; 6,561,977;6,755,784; 6,869,399; 6,908,432; 7,141,018; 7,230,012; 7,820,697;7,874,984; 7,959,566; 8,204,763; 8,315,886; 8,589,188; 8,626,531;8,673,939; 8,735,428; 8,741,929; 8,828,427; 9,056,120; 9,101,621; and9,101,622.

WO 2020/006262 filed by Dana Farber Cancer Institute discloses cereblonmodulators.

PCT/US19/24094 filed by C4 Therapeutics, Inc. discloses cereblon bindersfor degradation of Ikaros.

It is an object of the present invention to provide new compounds, usesand processes of manufacture that cause the degradation of Ikaros orAiolos for medical therapy, including for the treatment of hematopoieticdisorders that involve abnormal cellular proliferation, including tumorsand cancers.

SUMMARY OF THE INVENTION

New compounds are provided, along with their uses and manufacture thatbind cereblon. It is believed that binding of the disclosed compounds tocereblon results in increased interaction of cereblon with Ikaros(IKZF1) or Aiolos (IKZF3), leading to their subsequent ubiquitinationand degradation in the proteasome. Decreased levels of Ikaros or Aiolosleads to changes in transcriptional regulation of their downstreamproteins. The selected compounds are found to be both potent binders ofcereblon as well as showing potent inhibition of multiple myeloma cellproliferation as compared to pomalidomide.

A selected compound disclosed herein, its pharmaceutically acceptablesalt, or its pharmaceutically acceptable composition can be used to canbe used to treat a disorder mediated by Ikaros or Aiolos, for example, ahematopoietic malignancy such as multiple myeloma, leukemia, acutemyeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblasticleukemia, a myelodysplastic syndrome, or other target indications.Therefore, in one embodiment a method to treat a host (typically ahuman) with a disorder mediated by Ikaros or Aiolos is provided thatincludes administering an effective amount of the disclosed compound orits pharmaceutically acceptable salt described herein to the host,optionally as a pharmaceutically acceptable composition.

In one aspect, a compound is provided of Formula I:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition;

wherein:

X¹ and X² are independently selected from CH and N;

R¹ is selected from hydrogen, halogen, cyano, nitro, alkyl, haloalkyl,—NR²R^(2′), —OR², —NR²R⁴, —NR²R⁵, —OR⁵, —(CR³R^(3′))—R⁴,—(CR³R^(3′))—R⁵, —(CR³R^(3′))—NR²R⁴, —(CR³R^(3′))—NR²R⁵,—(CR³R^(3′))—OR⁴, —(CR³R^(3′))—OR⁵, —C(O)R⁴, —SR⁴, —SR⁵, —S(O)R⁴, and—S(O)₂R⁴;

R² and R^(2′) are independently selected at each occurrence fromhydrogen, alkyl, haloalkyl, cycloalkyl, heterocycle, aryl, heteroaryl,—C(O)R⁸, —C(O)OR⁸, —C(O)—NR⁸R^(8′), —S(O)R⁸, —SO₂R⁸, —SO₂—OR⁸, and—SO₂—NR⁸R^(8′);

R³ is selected from hydrogen, halogen, alkyl, haloalkyl, —OR⁸, and—NR⁸R^(8′);

R^(3′) is selected from hydrogen, halogen, alkyl, and haloalkyl;

or R³ and R^(3′) can be brought together with the carbon to which theyare attached to form a 3- to 6-membered cycloalkyl ring;

R⁴ is selected from cycloalkyl, heterocycle, aryl, and heteroaryl,wherein each R⁴ is optionally substituted with one group selected fromR⁶, and wherein each R⁴ is also optionally substituted with 1, 2, 3, or4 groups independently selected from R⁷;

R⁵ is —C(O)R⁶;

R⁶ is selected from alkyl, cycloalkyl, heterocycle, aryl, andheteroaryl, wherein each R⁶ is optionally substituted with 1, 2, 3, or 4groups independently selected from R⁹;

or R⁶ is selected from alkyl, cycloalkyl, heterocycle, aryl, heteroaryl,—CO-alkyl, —CO-cycloalkyl, —CO-heterocycle, —CO-aryl, —CO-heteroaryl,—O-alkyl, —O-cycloalkyl, —O-heterocycle, —O-aryl, —O-heteroaryl,—NR²-alkyl, —NR²-cycloalkyl, —NR²-heterocycle, —NR²-aryl, and—NR²-heteroaryl, wherein each R⁶ is optionally substituted with 1, 2, 3,or 4 groups independently selected from R⁹;

R⁷ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, aryl, heteroaryl, —OR⁸, —NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,—C(O)—NR⁸R^(8′), —OC(O)R⁸, —NR²—C(O)R⁸, —S(O)R⁸, —SO₂R⁸, —SO₂—OR⁸, and—SO₂—NR⁸R^(8′);

or two R⁷ on the same carbon may be brought together to form an oxogroup;

R⁸ and R^(8′) are independently selected at each occurrence fromhydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle,aryl, and heteroaryl;

R⁹ is independently selected at each occurrence from hydrogen, halogen,cyano, nitro, R¹⁰, —CH₂R¹⁰, —OR¹⁰, —NR²R¹⁰, —C(O)R¹⁰, —C(O)CH₂R¹⁰,—C(O)CH₂OR¹⁰, —C(O)CH₂NR²R¹⁰, —OC(O)R¹⁰, —NR²—C(O)R¹⁰, —C(O)OR¹⁰,—C(O)NR²R¹⁰, —S(O)R¹⁰, —SO₂R¹⁰, SO₂CH₂R¹⁰, —SO₂CH₂OR¹⁰, —SO₂CH₂NR²R¹⁰,—NR²SO₂—R¹⁰, —SO₂—OR¹⁰, and —SO₂—NR²R¹⁰;

R¹⁰ is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, aryl, and heteroaryl, wherein each R¹⁰ is optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R¹¹;and

R¹¹ is selected from: hydrogen; halogen; hydroxyl; cyano; nitro; alkyl;haloalkyl; alkenyl optionally substituted with an aryl or heteroarylgroup; alkynyl optionally substituted with an aryl or heteroaryl group;cycloalkyl; heterocycle; aryl optionally substituted with 1, 2, 3, or 4halogen, alkyl, or —OR⁸ groups; heteroaryl optionally substituted with1, 2, 3, or 4 halogen, alkyl, or —OR⁸ groups; —CH₂aryl optionallysubstituted with 1, 2, 3, or 4 halogen, alkyl, or —OR⁸ groups;—CH₂heteroaryl optionally substituted with 1, 2, 3, or 4 halogen, alkyl,or —OR⁸ groups; —OR⁸; —NR⁸R^(8′); —C(O)R⁸; —C(O)OR⁸; —C(O)—NR⁸R^(8′);—C(O)CH₂R⁸; —C(O)CH₂OR⁸; —C(O)CH₂—NR⁸R^(8′); —OC(O)R⁸; —NR²—C(O)R⁸;—CH₂—OC(O)R⁸; —CH₂—NR²—C(O)R⁸; —S(O)R⁸; —SO₂R⁸; —SO₂—OR⁸; and—SO₂—NR⁸R^(8′);

or two R¹¹ groups on the same carbon may be brought together to form anoxo group.

or R¹¹ is independently selected at each occurrence from: halogen;hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl;heterocycle; aryl; heteroaryl; —CH₂aryl; —CH₂heteroaryl; —OR⁸;—NR⁸R^(8′); —C(O)R⁸; —C(O)OR⁸; —C(O)—NR⁸R^(8′); —C(O)CH₂R⁸; —C(O)CH₂OR⁸;—C(O)CH₂—NR⁸R^(8′); —OC(O)R⁸; —NR²—C(O)R⁸; —CH₂—OC(O)R⁸;—CH₂—NR²—C(O)R⁸; —S(O)R⁸; —SO₂R⁸; —SO₂—OR⁸; oxo, and —SO₂—NR⁸R^(8′);each of which R¹¹ groups is optionally substituted with 1, 2, 3, or 4,groups independently selected from R¹²; and

R¹² is independently selected at each occurrence from: halogen;hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl;heterocycle; aryl; heteroaryl; —CH₂aryl; —CH₂heteroaryl; —OR⁸;—NR⁸R^(8′); —C(O)R⁸; —C(O)OR⁸; —C(O)—NR⁸R^(8′); —C(O)CH₂R⁸; —C(O)CH₂OR⁸;—C(O)CH₂—NR⁸R^(8′); —OC(O)R⁸; —NR²—C(O)R⁸; —CH₂—OC(O)R⁸;—CH₂—NR²—C(O)R⁸; —S(O)R⁸; —SO₂R⁸; —SO₂—OR⁸; and —SO₂—NR⁸R^(8′).

In one embodiment, the compound of Formula I is selected from FormulaI-a, Formula I-b, and Formula I-c:

wherein all variables are as defined herein.

In another embodiment, the compound of Formula I is selected fromFormula I-d, Formula I-e, Formula I-f, and Formula I-g:

wherein all variables are as defined herein.

In another aspect, the compound of Formula I is selected from FormulaI-h:

wherein all variables are as defined herein.

In one aspect a compound of Formula (II) is provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition;

wherein:

X³ is selected from bond, NR², C(R³R^(3′)), O, C(O), C(S), S, S(O), andS(O)₂;

R²⁰, R²¹, R²², R²³, and R²⁴ are independently at each occurrenceselected from the group consisting of a bond, alkyl, —C(O)—, —C(O)O—,—OC(O)—, —SO₂—, —S(O)—, —C(S)—, —C(O)NR²—, —NR²C(O)—, —O—, —S—, —NR²—,—P(O)(R²⁸)—, —P(O)—, alkene, alkyne, haloalkyl, aryl, heterocycle,heteroaryl, bicycle, and carbocycle; each of which is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁴⁰; and wherein R²⁰, R²¹, R²², R²³, and R²⁴ cannot be selected in sucha way that

-   -   i. —C(O)—, —C(O)O—, —OC(O)—, —SO₂—, —S(O)—, —P(O)(R²⁸)—, —P(O)—,        and —C(S)— moieties are adjacent to each other; or    -   ii. —O—, —S—, or —NR²— moieties are adjacent to each other; or    -   iii. moieties are otherwise selected in an order that an        unstable molecule results (as defined as producing a molecule        that has a shelf life at ambient temperature of less than about        four months (or alternatively less than about six or five        months) due to decomposition caused by the selection and order        of the moieties R²⁰, R²¹, R²², R²³, and R²⁴);

R²⁵ is selected from hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl,alkoxy, azide, amino, cyano, —OR², —NR²R^(2′), —NR²SO₂R²⁸, —OSO₂R²⁸,—SO₂R²⁸, haloalkyl, aryl, heteroaryl, heterocycle, bicycle, andcycloalkyl; each of which R²⁵ groups is optionally substituted with 1,2, 3, or 4 groups independently selected from R¹²;

R²⁸ independently selected at each occurrence from hydrogen, —NR²R^(2′),—OR², —SR², alkyl haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle,aryl, and heteroaryl;

R⁴⁰ is independently at each occurrence selected from the groupconsisting of hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl,alkoxy, azide, amino, cyano, —NR²R^(2′), —NR²SO₂R²⁸, —OSO₂R²⁸, —SO₂R²⁸,haloalkyl, aryl, heteroaryl, heterocycle, and cycloalkyl; each of whichR⁴⁰ groups is optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R¹²;

or two R⁴⁰s together form an oxo group;

and wherein all other variables are as defined herein.

In one embodiment, the compounds described herein bind to cereblon,increasing the interaction between cereblon and Ikaros (IKZF1) or Aiolos(IKZF3) and leading to the subsequent ubiquitination and degradation ofthe protein in the proteasome.

In one embodiment, the compound of the present invention selectivelydegrades IKZF1 and/or 3 over one or more of IKZF2 and/or 4 and/or 5.

In some embodiments, therefore, based on this discovery, compounds andmethods are provided for the treatment of a patient with a disordermediated by Ikaros (IKZF1) or Aiolos (IKZF3). Ikaros (IKZF1) or Aiolos(IKZF3) are targeted for selective degradation by a method that includesadministering an effective amount of a selective compound as describedherein alone or in combination with another active agent to a patient(typically a human) in need thereof, optionally in a pharmaceuticallyacceptable carrier to form a composition. In one embodiment, thedisorder is a lymphoid disorder. In one embodiment, the disorder is aleukemia. In one embodiment, the disorder is a lymphoid leukemia. In oneembodiment, the disorder is a lymphoblastic leukemia. In someembodiments, the disorder is a hematological malignancy, for examplemultiple myeloma, a myelodysplastic syndrome such as 5q-syndrome, acutelymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin'slymphoma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia. Inanother embodiment, a selected compound of the present invention isadministered to achieve immunomodulation and to reduce angiogenesis.

In other embodiments, compounds and methods are presented for thetreatment of a disorder including, but not limited to, benign growth,neoplasm, tumor, cancer, abnormal cellular proliferation, immunedisorders, inflammatory disorders, graft-versus-host rejection, viralinfection, bacterial infection, an amyloid-based proteinopathy, aproteinopathy, or a fibrotic disorder. Further, other disorders aredescribed below which can be treated with an effective amount of acompound described herein.

In certain embodiments, any of the compounds described herein have atleast one desired isotopic substitution of an atom, at an amount aboutthe natural abundance of the isotope, i.e., enriched. In one embodiment,the compound includes a deuterium or multiple deuterium atoms.

Other features and advantages of the present invention will be apparentfrom the following detailed description and claims.

Thus, the present invention includes at least the following features:

-   (a) a compound of Formula I or Formula II as described herein, or a    pharmaceutically acceptable salt, isotopic derivative (including a    deuterated derivative), or prodrug thereof;-   (b) a compound of Formula I or Formula II as described herein, or a    pharmaceutically acceptable salt, isotopic derivative, or prodrug    thereof, for the treatment of a disorder that is mediated by Ikaros    or Aiolos;-   (c) use of a compound of Formula I or Formula II as described    herein, or a pharmaceutically acceptable salt, isotopic derivative,    or prodrug thereof, in an effective amount in the treatment of a    patient, typically a human, with any one of the disorders described    herein, including those mediated by Ikaros or Aiolos;-   (d) use of a compound of Formula I or Formula II as described    herein, or a pharmaceutically acceptable salt, isotopic derivative,    or prodrug thereof in the manufacture of a medicament for the    treatment of a medical disorder sensitive to the compound, as    further described herein;-   (e) a method of manufacturing a medicament for the treatment of a    disorder described herein in a host characterized in that a compound    of Formula I or Formula II is used in the manufacture;-   (f) a compound of Formula I or Formula II as described herein, or a    pharmaceutically acceptable salt, isotopic derivative, or prodrug    thereof, for the treatment of cancer in a host, including any of the    cancers described herein;-   (g) use of a compound of Formula I or Formula II as described    herein, or a pharmaceutically acceptable salt, isotopic derivative,    or prodrug thereof in the manufacture of a medicament for the    treatment of cancer, including any of the cancers described herein;-   (h) a method of manufacturing a medicament for the treatment of    cancer in a host, including any of the cancers described herein,    characterized in that a compound of Formula I or Formula II is used    in the manufacture;-   (i) a compound of Formula I or Formula II as described herein, or a    pharmaceutically acceptable salt, isotopic derivative, or prodrug    thereof, for the treatment of a tumor in a host, including any of    the tumors described herein;-   (j) use of a compound of Formula I or Formula II as described    herein, or a pharmaceutically acceptable salt, isotopic derivative,    or prodrug thereof in the manufacture of a medicament for the    treatment of a tumor, including any of the tumors described herein;-   (k) a method of manufacturing a medicament for the treatment of a    tumor in a host, including any of the tumors described herein,    characterized in that a compound of Formula I or Formula II is used    in the manufacture;-   (l) a compound of Formula I or Formula II as described herein, or a    pharmaceutically acceptable salt, isotopic derivative, or prodrug    thereof, for the treatment of an immune, autoimmune, or inflammatory    disorder in a host;-   (m) use of a compound of Formula I or Formula II as described    herein, or a pharmaceutically acceptable salt, isotopic derivative,    or prodrug thereof in the manufacture of a medicament for the    treatment of an immune, autoimmune, or inflammatory disorder;-   (n) a method of manufacturing a medicament for the treatment of an    immune, autoimmune, or inflammatory disorder in a host characterized    in that a compound of Formula I or Formula II is used in the    manufacture;-   (o) a compound of Formula I or Formula II as described herein, or a    pharmaceutically acceptable salt, isotopic derivative, or prodrug    thereof, for the treatment of a hematological malignancy such as    multiple myeloma, leukemia, lymphoblastic leukemia, chronic    lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma;-   (p) use of a compound of Formula I or Formula II as described    herein, or a pharmaceutically acceptable salt, isotopic derivative,    or prodrug thereof in the manufacture of a medicament for the    treatment of a hematological malignancy such as multiple myeloma,    leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia,    Hodgkin's lymphoma, or non-Hodgkin's lymphoma;-   (q) a method of manufacturing a medicament for the treatment of a    hematological malignancy in a host such as multiple myeloma,    leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia,    Hodgkin's lymphoma, or non-Hodgkin's lymphoma, characterized in that    a compound of Formula I or Formula II is used in the manufacture;-   (r) a pharmaceutical composition comprising an effective    host-treating amount of a compound of Formula I or Formula II as    described herein or a pharmaceutically acceptable salt, isotopic    derivative, or prodrug thereof with a pharmaceutically acceptable    carrier or diluent;-   (s) a compound a described herein as a mixture of enantiomers or    diastereomers (as relevant), including the racemate;-   (t) a compound as described herein in enantiomerically or    diastereomerically (as relevant) enriched form, including an    isolated enantiomer or diastereomer (i.e. greater than 85, 90, 95,    97, or 99% pure); and-   (u) a process for the e of therapeutic products that contain an    effective amount of a compound of Formula I or Formula II as    described herein.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this application belongs. In the specification,singular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice and testing of thepresent application, suitable methods and materials are described below.All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the claimed application. Inthe case of conflict, the present specification, including definitions,will control. In addition, the materials, methods, and examples areillustrative only and are not intended to be limiting.

Compounds are described using standard nomenclature. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

In one embodiment of each compound described herein, the compound may bein the form of a racemate, enantiomer, mixture of enantiomers,diastereomer, mixture of diastereomers, tautomer, N-oxide, or isomer,such as a rotamer, as if each is specifically described unlessspecifically excluded by context.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. Recitation of ranges of values are merelyintended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The endpoints of all rangesare included within the range and independently combinable. All methodsdescribed herein can be performed in a suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof examples, or exemplary language (e.g., “such as”), is intended merelyto better illustrate the invention and does not pose a limitation on thescope of the invention unless otherwise claimed.

The present invention includes compounds described herein with at leastone desired isotopic substitution of an atom, at an amount above thenatural abundance of the isotope, i.e., enriched. Isotopes are atomshaving the same atomic number but different mass numbers, i.e., the samenumber of protons but a different number of neutrons. If isotopicsubstitutions are used, the common replacement is at least one deuteriumfor hydrogen.

More generally, examples of isotopes that can be incorporated intocompounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, fluorine, and chlorine such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C,¹⁵N, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, and ³⁶Cl respectively. In one non-limitingembodiment, isotopically labelled compounds can be used in metabolicstudies (with, for example ¹⁴C) reaction kinetic studies (with, forexample ²H or ³H), detection or imaging techniques, such as positronemission tomography (PET) or single-photon emission computed tomography(SPECT) including drug or substrate tissue distribution assays, or inradioactive treatment of patients. Additionally, any hydrogen atompresent in the compound of the invention may be substituted with an ¹⁸Fatom, a substitution that may be particularly desirable for PET or SPECTstudies. Isotopically labeled compounds of this invention and prodrugsthereof can generally be prepared by carrying out the proceduresdisclosed in the schemes or in the examples and preparations describedbelow by substituting a readily available isotopically labeled reagentfor a non-isotopically labeled reagent.

By way of general example and without limitation, isotopes of hydrogen,for example, deuterium (²H) and tritium (³H) may be used anywhere indescribed structures that achieves the desired result. Alternatively orin addition, isotopes of carbon, e.g., ¹³C and ¹⁴C, may be used.

Isotopic substitutions, for example deuterium substitutions, can bepartial or complete. Partial deuterium substitution means that at leastone hydrogen is substituted with deuterium. In certain embodiments, theisotope is 90, 95 or 99% or more enriched in an isotope at any locationof interest. In one non-limiting embodiment, deuterium is 90, 95 or 99%enriched at a desired location.

In one non-limiting embodiment, the substitution of a hydrogen atom fora deuterium atom can be provided in any compound described herein. Forexample, when any of the groups are, or contain for example throughsubstitution, methyl, ethyl, or methoxy, the alkyl residue may bedeuterated (in non-limiting embodiments, CDH₂, CD₂H, CD₃, CH₂CD₃,CD₂CD₃, CHDCH₂D, CH₂CD₃, CHDCHD₂, OCDH₂, OCD₂H, or OCD₃ etc.). Incertain other embodiments, when two substituents are combined to form acycle the unsubstituted carbons may be deuterated. In one embodiment, atleast one deuterium is placed on an atom that has a bond which is brokenduring metabolism of the compound in vivo, or is one, two or three atomsremote form the metabolized bond (e.g., which may be referred to as anα, β or γ, or primary, secondary or tertiary isotope effect).

The compounds of the present invention may form a solvate with a solvent(including water). Therefore, in one non-limiting embodiment, theinvention includes a solvated form of the compounds described herein.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including a salt thereof) with one or more solventmolecules. Non-limiting examples of solvents are water, ethanol,isopropanol, dimethyl sulfoxide, acetone and other common organicsolvents. The term “hydrate” refers to a molecular complex comprising acompound of the invention and water. Pharmaceutically acceptablesolvates in accordance with the invention include those wherein thesolvent may be isotopically substituted, e.g. D₂O, d₆-acetone, d₆-DMSO.A solvate can be in a liquid or solid form.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —(C═O)NH₂is attached through carbon of the keto (C═O) group.

“Alkyl” is a branched or straight chain saturated aliphatic hydrocarbongroup. In one non-limiting embodiment, the alkyl group contains from 1to about 12 carbon atoms, more generally from 1 to about 6 carbon atomsor from 1 to about 4 carbon atoms. In one non-limiting embodiment, thealkyl contains from 1 to about 8 carbon atoms. In certain embodiments,the alkyl is C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, or C₁-C₆. The specified rangesas used herein indicate an alkyl group having each member of the rangedescribed as an independent species. For example, the term C₁-C₆ alkylas used herein indicates a straight or branched alkyl group having from1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each ofthese is described as an independent species. For example, the termC₁-C₄ alkyl as used herein indicates a straight or branched alkyl grouphaving from 1, 2, 3, or 4 carbon atoms and is intended to mean that eachof these is described as an independent species. Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl,neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane,2,2-dimethylbutane, and 2,3-dimethylbutane.

“Alkenyl” is a linear or branched aliphatic hydrocarbon groups havingone or more carbon-carbon double bonds that may occur at a stable pointalong the chain. The specified ranges as used herein indicate an alkenylgroup having each member of the range described as an independentspecies, as described above for the alkyl moiety. In one non-limitingembodiment, the alkenyl contains from 2 to about 12 carbon atoms, moregenerally from 2 to about 6 carbon atoms or from 2 to about 4 carbonatoms. In certain embodiments the alkenyl is C₂, C₂-C₃, C₂-C₄, C₂-C₅, orC₂-C₆. Examples of alkenyl radicals include, but are not limited toethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. Theterm “alkenyl” also embodies “cis” and “trans” alkenyl geometry, oralternatively, “E” and “Z” alkenyl geometry. The term “Alkenyl” alsoencompasses cycloalkyl or carbocyclic groups possessing at least onepoint of unsaturation.

“Alkynyl” is a branched or straight chain aliphatic hydrocarbon grouphaving one or more carbon-carbon triple bonds that may occur at anystable point along the chain. The specified ranges as used hereinindicate an alkynyl group having each member of the range described asan independent species, as described above for the alkyl moiety. In onenon-limiting embodiment, the alkynyl contains from 2 to about 12 carbonatoms, more generally from 2 to about 6 carbon atoms or from 2 to about4 carbon atoms. In certain embodiments the alkynyl is C₂, C₂-C₃, C₂-C₄,C₂-C₅, or C₂-C₆. Examples of alkynyl include, but are not limited to,ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,4-hexynyl and 5-hexynyl.

“Halo” and “Halogen” is independently fluorine, chlorine, bromine oriodine.

“Haloalkyl” is a branched or straight-chain alkyl groups substitutedwith 1 or more halo atoms described above, up to the maximum allowablenumber of halogen atoms. Examples of haloalkyl groups include, but arenot limited to, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.“Perhaloalkyl” means an alkyl group having all hydrogen atoms replacedwith halogen atoms. Examples include but are not limited to,trifluoromethyl and pentafluoroethyl.

As used herein, “aryl” refers to a radical of a monocyclic or polycyclic(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6,10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbonatoms and zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1 naphthyl and2naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems whereinthe aryl ring, as defined above, is fused with one or more cycloalkyl orheterocycle groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. The one ormore fused cycloalkyl or heterocycle groups can be a 4 to 7-memberedsaturated or partially unsaturated cycloalkyl or heterocycle groups.

The term “heterocycle” denotes saturated and partially saturatedheteroatom-containing ring radicals, wherein there are 1, 2, 3, or 4heteroatoms independently selected from nitrogen, sulfur, boron,silicone, and oxygen. Heterocyclic rings may comprise monocyclic 3-10membered rings, as well as 5-16 membered bicyclic ring systems (whichcan include bridged, fused, and spiro-fused bicyclic ring systems). Itdoes not include rings containing —O—O—, —O—S— or —S—S— portions.Examples of saturated heterocycle groups include saturated 3- to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocycle radicalsinclude but are not limited to, dihydrothienyl, dihydropyranyl,dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated andsaturated heterocycle groups include but are not limited to,pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl,dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl,1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl.

“Heterocycle” also includes groups wherein the heterocyclic radical isfused/condensed with an aryl or carbocycle radical, wherein the point ofattachment is the heterocycle ring. “Heterocycle” also includes groupswherein the heterocyclic radical is substituted with an oxo group

For example a partially unsaturated condensed heterocyclic groupcontaining 1 to 5 nitrogen atoms, for example, indoline or isoindoline;a partially unsaturated condensed heterocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms; a partially unsaturatedcondensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms; and a saturated condensed heterocyclic group containing1 to 2 oxygen or sulfur atoms.

The term “heterocycle” also includes “bicyclic heterocycle”. The term“bicyclic heterocycle” denotes a heterocycle as defined herein whereinthere is one bridged, fused, or spirocyclic portion of the heterocycle.The bridged, fused, or spirocyclic portion of the heterocycle can be acarbocycle, heterocycle, or aryl group as long as a stable moleculeresults. Unless excluded by context the term “heterocycle” includesbicyclic heterocycles. Bicyclic heterocycle includes groups wherein thefused heterocycle is substituted with an oxo group. Non-limitingexamples of bicyclic heterocycles include:

The term “heteroaryl” denotes stable aromatic ring systems that contain1, 2, 3, or 4 heteroatoms independently selected from O, N, and S,wherein the ring nitrogen and sulfur atom(s) are optionally oxidized,and nitrogen atom(s) are optionally quarternized. Examples include butare not limited to, unsaturated 5 to 6 membered heteromonocyclyl groupscontaining 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclicgroups containing an oxygen atom, for example, pyranyl, 2-furyl,3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic groupscontaining a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupscontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl]. In one embodiment the “heteroaryl” group is a 8, 9,or 10 membered bicyclic ring system. Examples of 8, 9, or 10 memberedbicyclic heteroaryl groups include benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl,indazolyl, and benzotriazolyl.

As used herein, “carbocyclic”, “carbocycle” or “cycloalkyl” includes asaturated or partially unsaturated (i.e., not aromatic) group containingall carbon ring atoms and from 3 to 14 ring carbon atoms (“C₃₋₁₄cycloalkyl”) and zero heteroatoms in the nonaromatic ring system. Insome embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms(“C₃₋₁₀ cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 9ring carbon atoms (“C₃₋₉ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ cycloalkyl”). In someembodiments, a cycloalkyl group has 3 to 7 ring carbon atoms (“C₃₋₇cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ringcarbon atoms (“C₃₋₆ cycloalkyl”). In some embodiments, a cycloalkylgroup has 4 to 6 ring carbon atoms (“C₄₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Exemplary C₃₋₆ cycloalkyl groupsinclude, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃),cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl(C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and thelike. Exemplary C₃₋₈ cycloalkyl groups include, without limitation, theaforementioned C₃₋₆ cycloalkyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), and the like. Exemplary C₃₋₁₀cycloalkyl groups include, without limitation, the aforementioned C₃₋₈cycloalkyl groups as well as cyclononyl (C₉), cyclononenyl (C₉),cyclodecyl (C₁₀), cyclodecenyl (C₁₀), and the like. As the foregoingexamples illustrate, in certain embodiments, the cycloalkyl group can besaturated or can contain one or more carboncarbon double bonds. The term“cycloalkyl” also includes ring systems wherein the cycloalkyl ring, asdefined above, is fused with one heterocycle, aryl or heteroaryl ringwherein the point of attachment is on the cycloalkyl ring, and in suchinstances, the number of carbons continue to designate the number ofcarbons in the carbocyclic ring system. The term “cycloalkyl” alsoincludes ring systems wherein the cycloalkyl ring, as defined above, hasa spirocyclic heterocycle, aryl or heteroaryl ring wherein the point ofattachment is on the cycloalkyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. The term “cycloalkyl” also includes bicyclic orpolycyclic fused, bridged, or spiro ring systems that contain from 5 to14 carbon atoms and zero heteroatoms in the non-aromatic ring system.Representative examples of “cycloalkyl” include, but are not limited to,

The term “bicycle” refers to a ring system wherein two rings are fusedtogether and each ring is independently selected from carbocycle,heterocycle, aryl, and heteroaryl. Non-limiting examples of bicyclegroups include:

When the term “bicycle” is used in the context of a bivalent residuesuch as R²⁰, R²¹, R²², R²³, or R²⁴, the attachment points can be onseparate rings or on the same ring. In certain embodiments bothattachment points are on the same ring. In certain embodiments bothattachment points are on different rings. Non-limiting examples ofbivalent bicycle groups include:

A “dosage form” means a unit of administration of an active agent.Examples of dosage forms include tablets, capsules, injections,suspensions, liquids, emulsions, implants, particles, spheres, creams,ointments, suppositories, inhalable forms, transdermal forms, buccal,sublingual, topical, gel, mucosal, and the like. A “dosage form” canalso include an implant, for example an optical implant.

As used herein “endogenous” refers to any material from or producedinside an organism, cell, tissue or system.

As used herein, the term “exogenous” refers to any material introducedfrom or produced outside an organism, cell, tissue or system.

By the term “modulating,” as used herein, is meant mediating adetectable increase or decrease in the level of a response in a subjectcompared with the level of a response in the subject in the absence of atreatment or compound, and/or compared with the level of a response inan otherwise identical but untreated subject. The term encompassesperturbing and/or affecting a native signal or response therebymediating a beneficial therapeutic response in a subject, preferably, ahuman.

“Parenteral” administration of a compound includes, e.g., subcutaneous(s.c.), intravenous (i.v.), intramuscular (i.m.), or intrasternalinjection, or infusion techniques.

As used herein, “pharmaceutical compositions” is a compositioncomprising at least one active agent such as a selected active compoundas described herein, and at least one other substance, such as acarrier. “Pharmaceutical combinations” are combinations of at least twoactive agents which may be combined in a single dosage form or providedtogether in separate dosage forms with instructions that the activeagents are to be used together to treat any disorder described herein.

As used herein, a “pharmaceutically acceptable salt” is a derivative ofthe disclosed compound in which the parent compound is modified bymaking inorganic and organic, acid or base addition salts thereof with abiologically acceptable lack of toxicity. The salts of the presentcompounds can be synthesized from a parent compound that contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting free acid forms of these compoundswith a stoichiometric amount of the appropriate base (such as Na, Ca,Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reactingfree base forms of these compounds with a stoichiometric amount of theappropriate acid. Such reactions are typically carried out in water orin an organic solvent, or in a mixture of the two. Generally,non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are typical, where practicable. Salts of the presentcompounds further include solvates of the compounds and of the compoundsalts.

Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts and the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic acid salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like, or using a differentacid that produces the same counterion. Lists of additional suitablesalts may be found, e.g., in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

The term “carrier” means a diluent, excipient, or vehicle that an activeagent is used or delivered in.

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition/combination that isgenerally safe, and neither biologically nor otherwise inappropriate foradministration to a host, typically a human. In one embodiment, anexcipient is used that is acceptable for veterinary use.

A “patient” or “host” or “subject” is a human or non-human animal inneed of treatment, of any of the disorders as specifically describedherein. Typically, the host is a human. A “host” may alternatively referto for example, a mammal, primate (e.g., human), cow, sheep, goat,horse, dog, cat, rabbit, rat, mice, fish, bird and the like.

A “therapeutically effective amount” of a pharmaceuticalcomposition/combination of this invention means an amount effective,when administered to a host, to provide a therapeutic benefit such as anamelioration of symptoms or reduction or diminution of the diseaseitself.

Throughout this disclosure, various aspects of the invention can bepresented in a range format. It should be understood that thedescription in range format is merely for convenience and should not beconstrued as a limitation on the scope of the invention. The descriptionof a range should be considered to have specifically disclosed all thepossible subranges as well as individual numerical values within thatrange. For example, description of a range such as from 1 to 6 should beconsidered to have specifically disclosed subranges such as from 1 to 3,from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., aswell as individual numbers within that range, for example, 1, 2, 2.7, 3,4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

II. Compounds of the Present Invention Embodiments of “Alkyl”

In one embodiment “alkyl” is a C₁-C₁₀alkyl, C₁-C₉alkyl, C₁-C₈alkyl,C₁-C₇alkyl, C₁-C₆alkyl, C₁-C₅alkyl, C₁-C₄alkyl, C₁-C₃alkyl, orC₁-C₂alkyl.

In one embodiment “alkyl” has one carbon.

In one embodiment “alkyl” has two carbons.

In one embodiment “alkyl” has three carbons.

In one embodiment “alkyl” has four carbons.

In one embodiment “alkyl” has five carbons.

In one embodiment “alkyl” has six carbons.

Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl,pentyl, and hexyl.

Additional non-limiting examples of “alkyl” include: isopropyl,isobutyl, isopentyl, and isohexyl.

Additional non-limiting examples of “alkyl” include: sec-butyl,sec-pentyl, and sec-hexyl.

Additional non-limiting examples of “alkyl” include: tert-butyl,tert-pentyl, and tert-hexyl.

Additional non-limiting examples of “alkyl” include: neopentyl,3-pentyl, and active pentyl.

Embodiments of “Haloalkyl”

In one embodiment “haloalkyl” is a C₁-C₁₀haloalkyl, C₁-C₉haloalkyl,C₁-C₈haloalkyl, C₁-C₇haloalkyl, C₁-C₆haloalkyl, C₁-C₅haloalkyl,C₁-C₄haloalkyl, C₁-C₃haloalkyl, and C₁-C₂haloalkyl.

In one embodiment “haloalkyl” has one carbon.

In one embodiment “haloalkyl” has one carbon and one halogen.

In one embodiment “haloalkyl” has one carbon and two halogens.

In one embodiment “haloalkyl” has one carbon and three halogens.

In one embodiment “haloalkyl” has two carbons.

In one embodiment “haloalkyl” has three carbons.

In one embodiment “haloalkyl” has four carbons.

In one embodiment “haloalkyl” has five carbons.

In one embodiment “haloalkyl” has six carbons.

Non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include:

Embodiments of “Aryl”

In one embodiment “aryl” is a 6 carbon aromatic group (phenyl)

In one embodiment “aryl” is a 10 carbon aromatic group (napthyl)

In one embodiment “aryl” is a 6 carbon aromatic group fused to aheterocycle wherein the point of attachment is the aryl ring.Non-limiting examples of “aryl” include indoline, tetrahydroquinoline,tetrahydroisoquinoline, and dihydrobenzofuran wherein the point ofattachment for each group is on the aromatic ring.

For example,

is an “aryl” group.

However,

is a “heterocycle” group.

In one embodiment “aryl” is a 6 carbon aromatic group fused to acycloalkyl wherein the point of attachment is the aryl ring.Non-limiting examples of “aryl” include dihydro-indene andtetrahydronaphthalene wherein the point of attachment for each group ison the aromatic ring.

For example,

is an “aryl” group.

However,

is a “cycloalkyl” group.

Embodiments of “Heteroaryl”

In one embodiment “heteroaryl” is a 5 membered aromatic group containing1, 2, 3, or 4 nitrogen atoms.

Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole,furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole,oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole,and thiatriazole.

Additional non-limiting examples of 5 membered “heteroaryl” groupsinclude:

In one embodiment “heteroaryl” is a 6 membered aromatic group containing1, 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl,pyrimidinyl, and pyrazinyl).

Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2nitrogen atoms include:

In one embodiment “heteroaryl” is a 9 membered bicyclic aromatic groupcontaining 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of “heteroaryl” groups that are bicyclic includeindole, benzofuran, isoindole, indazole, benzimidazole, azaindole,azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole,benzoisothiazole, benzooxazole, and benzothiazole.

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

In one embodiment “heteroaryl” is a 10 membered bicyclic aromatic groupcontaining 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of “heteroaryl” groups that are bicyclic includequinoline, isoquinoline, quinoxaline, phthalazine, quinazoline,cinnoline, and naphthyridine.

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

Embodiments of “Cycloalkyl”

In one embodiment “cycloalkyl” is a C₃-C₈cycloalkyl, C₃-C₇cycloalkyl,C₃-C₆cycloalkyl, C₃-C₅cycloalkyl, C₃-C₄cycloalkyl, C₄-C₈cycloalkyl,C₅-C₈cycloalkyl, or C₆-C₈cycloalkyl.

In one embodiment “cycloalkyl” has three carbons.

In one embodiment “cycloalkyl” has four carbons.

In one embodiment “cycloalkyl” has five carbons.

In one embodiment “cycloalkyl” has six carbons.

In one embodiment “cycloalkyl” has seven carbons.

In one embodiment “cycloalkyl” has eight carbons.

In one embodiment “cycloalkyl” has nine carbons.

In one embodiment “cycloalkyl” has ten carbons.

Non-limiting examples of “cycloalkyl” include: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

Additional non-limiting examples of “cycloalkyl” include dihydro-indeneand tetrahydronaphthalene wherein the point of attachment for each groupis on the cycloalkyl ring.

For example

is an “cycloalkyl” group.

However,

is an “aryl” group.

Additional examples of “cycloalkyl” groups include

and

Embodiments of “Heterocycle”

In one embodiment “heterocycle” refers to a cyclic ring with onenitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with onenitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with twonitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with one oxygenand 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with one sulfurand 3, 4, 5, 6, 7, or 8 carbon atoms.

Non-limiting examples of “heterocycle” include aziridine, oxirane,thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

Additional non-limiting examples of “heterocycle” include pyrrolidine,3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

Additional non-limiting examples of “heterocycle” includetetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane,and 1,3-oxathiolane.

Additional non-limiting examples of “heterocycle” include piperidine,piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane,1,4-dithiane, morpholine, and thiomorpholine.

Additional non-limiting examples of “heterocycle” include indoline,tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuranwherein the point of attachment for each group is on the heterocyclicring.

For example,

is a “heterocycle” group.

However,

is an “aryl” group.

Non-limiting examples of “heterocycle” also include:

Additional non-limiting examples of “heterocycle” include:

Additional non-limiting examples of “heterocycle” include:

Non-limiting examples of “heterocycle” also include:

Non-limiting examples of “heterocycle” also include:

Additional non-limiting examples of “heterocycle” include:

Additional non-limiting examples of “heterocycle” include:

Optional Substituents

In one embodiment a moiety described herein that can be substituted with1, 2, 3, or 4 substituents is substituted with one substituent.

In one embodiment a moiety described herein that can be substituted with1, 2, 3, or 4 substituents is substituted with two substituents.

In one embodiment a moiety described herein that can be substituted with1, 2, 3, or 4 substituents is substituted with three substituents.

In one embodiment a moiety described herein that can be substituted with1, 2, 3, or 4 substituents is substituted with four substituents.

Non-Limiting Embodiments of the Tricyclic Core

The tricyclic core moiety has 1, 2, or 3 nitrogens.

In one embodiment, the compound of Formula I is selected from:

Non-Limiting Embodiments of Formula I

In certain embodiments the compound of the present invention is selectedfrom Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

Non-Limiting Embodiments of IV

In one embodiment of Formula I, R¹ is selected from —NH(cycloalkylsubstituted with R⁶). In one embodiment of Formula I, R¹ is selectedfrom —NH(heterocycle substituted with R⁶). In one embodiment of FormulaI, R¹ is selected from —NH(aryl substituted with R⁶). In one embodimentof Formula I, R¹ is selected from —NH(heteroaryl substituted with R⁶).In one embodiment of Formula I, R¹ is selected from N(CH₃)(cycloalkylsubstituted with R⁶). In one embodiment of Formula I, R¹ is selectedfrom N(CH₃)(heterocycle substituted with R⁶). In one embodiment ofFormula I, R¹ is selected from N(CH₃)(aryl substituted with R⁶). In oneembodiment of Formula I, R¹ is selected from N(CH₃)(heteroarylsubstituted with R⁶).

In one embodiment of Formula I, R¹ is selected from —O(cycloalkylsubstituted with R⁶). In one embodiment of Formula I, R¹ is selectedfrom —O(heterocycle substituted with R⁶). In one embodiment of FormulaI, R¹ is selected from —O(aryl substituted with R⁶). In one embodimentof Formula I, R¹ is selected from —O(heteroaryl substituted with R⁶).

In one embodiment of Formula I, R¹ is selected from —S(cycloalkylsubstituted with R⁶). In one embodiment of Formula I, R¹ is selectedfrom —S(heterocycle substituted with R⁶). In one embodiment of FormulaI, R¹ is selected from —S(aryl substituted with R⁶). In one embodimentof Formula I, R¹ is selected from —S(heteroaryl substituted with R⁶).

In one embodiment of Formula I, R¹ is selected from NH—C(O)-(alkyl). Inone embodiment of Formula I, R¹ is selected from NH—C(O)-(cycloalkyl).In one embodiment of Formula I, R¹ is selected fromNH—C(O)-(heterocycle). In one embodiment of Formula I, R¹ is selectedfrom NH—C(O)-(aryl). In one embodiment of Formula I, R¹ is selected fromNH—C(O)-(heteroaryl). In one embodiment of Formula I, R¹ is selectedfrom N(CH₃)—C(O)-(alkyl). In one embodiment of Formula I, R¹ is selectedfrom N(CH₃)—C(O)-(cycloalkyl). In one embodiment of Formula I, R¹ isselected from N(CH₃)—C(O)-(heterocycle). In one embodiment of Formula I,R¹ is selected from N(CH₃)—C(O)-(aryl). In one embodiment of Formula I,R¹ is selected from N(CH₃)—C(O)-(heteroaryl).

In one embodiment of Formula I, R¹ is selected from O—C(O)-(alkyl). Inone embodiment of Formula I, R¹ is selected from O—C(O)-(cycloalkyl). Inone embodiment of Formula I, R¹ is selected from O—C(O)-(heterocycle).In one embodiment of Formula I, R¹ is selected from —O—C(O)-(aryl). Inone embodiment of Formula I, R¹ is selected from —O—C(O)-(heteroaryl).

In one embodiment of Formula I, R¹ is selected from S—C(O)-(alkyl). Inone embodiment of Formula I, R¹ is selected from S—C(O)-(cycloalkyl). Inone embodiment of Formula I, R¹ is selected from —S—C(O)-(heterocycle).In one embodiment of Formula I, R¹ is selected from —S—C(O)-(aryl). Inone embodiment of Formula I, R¹ is selected from —S—C(O)-(heteroaryl).

In one embodiment of Formula I, R¹ is selected from —CH₂(cycloalkylsubstituted with R⁶). In one embodiment of Formula I, R¹ is selectedfrom —CH₂(heterocycle substituted with R⁶). In one embodiment of FormulaI, R¹ is selected from —CH₂(aryl substituted with R⁶). In one embodimentof Formula I, R¹ is selected from —CH₂(heteroaryl substituted with R⁶).In one embodiment of Formula I, R¹ is selected from —CF₂(cycloalkylsubstituted with R⁶). In one embodiment of Formula I, R¹ is selectedfrom —CF₂(heterocycle substituted with R⁶). In one embodiment of FormulaI, R¹ is selected from —CF₂(aryl substituted with R⁶). In one embodimentof Formula I, R¹ is selected from —CF₂(heteroaryl substituted with R⁶).In one embodiment of Formula I, R¹ is selected from —CH(OH)(cycloalkylsubstituted with R⁶). In one embodiment of Formula I, R¹ is selectedfrom —CH(OH)(heterocycle substituted with R⁶). In one embodiment ofFormula I, R¹ is selected from —CH(OH)(aryl substituted with R⁶). In oneembodiment of Formula I, R¹ is selected from —CH(OH)(heteroarylsubstituted with R⁶).

In one embodiment of Formula I, R¹ is selected from —CH₂—C(O)-(alkyl).In one embodiment of Formula I, R¹ is selected from—CH₂—C(O)-(cycloalkyl). In one embodiment of Formula I, R¹ is selectedfrom —CH₂—C(O)-(heterocycle). In one embodiment of Formula I, R¹ isselected from —CH₂—C(O)-(aryl). In one embodiment of Formula I, R¹ isselected from —CH₂—C(O)-(heteroaryl). In one embodiment of Formula I, R¹is selected from —CF₂—C(O)-(alkyl). In one embodiment of Formula I, R¹is selected from —CF₂—C(O)-(cycloalkyl). In one embodiment of Formula I,R¹ is selected from —CF₂—C(O)-(heterocycle). In one embodiment ofFormula I, R¹ is selected from —CF₂—C(O)-(aryl). In one embodiment ofFormula I, R¹ is selected from —CF₂—C(O)-(heteroaryl). In one embodimentof Formula I, R¹ is selected from —CH(OH)—C(O)-(alkyl). In oneembodiment of Formula I, R¹ is selected from —CH(OH)—C(O)-(cycloalkyl).In one embodiment of Formula I, R¹ is selected from—CH(OH)—C(O)-(heterocycle). In one embodiment of Formula I, R¹ isselected from —CH(OH)—C(O)-(aryl). In one embodiment of Formula I, R¹ isselected from —CH(OH)—C(O)-(heteroaryl).

In one embodiment of Formula I, R¹ is selected from —CH₂—NH(cycloalkylsubstituted with R⁶). In one embodiment of Formula I, R¹ is selectedfrom —CH₂—NH(heterocycle substituted with R⁶). In one embodiment ofFormula I, R¹ is selected from —CH₂—NH(aryl substituted with R⁶). In oneembodiment of Formula I, R¹ is selected from —CH₂—NH(heteroarylsubstituted with R⁶). In one embodiment of Formula I, R¹ is selectedfrom —CH₂N(CH₃)(cycloalkyl substituted with R⁶). In one embodiment ofFormula I, R¹ is selected from —CH₂N(CH₃)(heterocycle substituted withR⁶). In one embodiment of Formula I, R¹ is selected from —CH₂N(CH₃)(arylsubstituted with R⁶). In one embodiment of Formula I, R¹ is selectedfrom —CH₂N(CH₃)(heteroaryl substituted with R⁶).

In one embodiment of Formula I, R¹ is selected from —CH₂—O(cycloalkylsubstituted with R⁶). In one embodiment of Formula I, R¹ is selectedfrom —CH₂—O(heterocycle substituted with R⁶). In one embodiment ofFormula I, R¹ is selected from —CH₂—O(aryl substituted with R⁶). In oneembodiment of Formula I, R¹ is selected from —CH₂—O(heteroarylsubstituted with R⁶).

In one embodiment of Formula I, R¹ is selected from —CH₂NH—C(O)-(alkyl).In one embodiment of Formula I, R¹ is selected from—CH₂NH—C(O)-(cycloalkyl). In one embodiment of Formula I, R¹ is selectedfrom —CH₂NH—C(O)-(heterocycle). In one embodiment of Formula I, R¹ isselected from —CH₂NH—C(O)-(aryl). In one embodiment of Formula I, R¹ isselected from —CH₂NH—C(O)-(heteroaryl). In one embodiment of Formula I,R¹ is selected from —CH₂N(CH₃)—C(O)-(alkyl). In one embodiment ofFormula I, R¹ is selected from —CH₂N(CH₃)—C(O)-(cycloalkyl). In oneembodiment of Formula I, R¹ is selected from—CH₂N(CH₃)—C(O)-(heterocycle). In one embodiment of Formula I, R¹ isselected from —CH₂N(CH₃)—C(O)-(aryl). In one embodiment of Formula I, R¹is selected from —CH₂N(CH₃)—C(O)-(heteroaryl).

In one embodiment of Formula I, R¹ is selected from —CH₂—O—C(O)-(alkyl).In one embodiment of Formula I, R¹ is selected from—CH₂—O—C(O)-(cycloalkyl). In one embodiment of Formula I, R¹ is selectedfrom —CH₂—O—C(O)-(heterocycle). In one embodiment of Formula I, le isselected from —CH₂—O—C(O)-(aryl). In one embodiment of Formula I, R¹ isselected from —CH₂—O—C(O)-(heteroaryl).

In one embodiment of Formula I, R¹ is selected from C(O)-(cycloalkylsubstituted with R⁶). In one embodiment of Formula I, R¹ is selectedfrom —C(O)-(heterocycle substituted with R⁶). In one embodiment ofFormula I, R¹ is selected from —C(O)-(aryl substituted with R⁶). In oneembodiment of Formula I, R¹ is selected from —C(O)-(heteroarylsubstituted with R⁶).

In one embodiment of Formula I, R¹ is selected from —S(O)-(cycloalkylsubstituted with R⁶). In one embodiment of Formula I, R¹ is selectedfrom —S(O)-(heterocycle substituted with R⁶). In one embodiment ofFormula I, R¹ is selected from —S(O)-(aryl substituted with R⁶). In oneembodiment of Formula I, R¹ is selected from —S(O)-(heteroarylsubstituted with R⁶).

In one embodiment of Formula I, R¹ is selected from —S(O)₂-(cycloalkylsubstituted with R⁶). In one embodiment of Formula I, R¹ is selectedfrom —S(O)₂-(heterocycle substituted with R⁶). In one embodiment ofFormula I, R¹ is selected from —S(O)₂-(aryl substituted with R⁶). In oneembodiment of Formula I, R¹ is selected from —S(O)₂-(heteroarylsubstituted with R⁶).

In one embodiment of Formula I, R¹ is selected from:

In certain embodiments, R¹ is selected from halogen, hydrogen, amino, orcyano. In one embodiment, R¹ is bromine.

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from hydrogen and alkyl. Non-limitingexamples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from alkyl and —C(CH₂)R¹⁰ wherein R¹⁰ isheterocycle. Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from alkyl and —C(O)R¹⁰ wherein R¹⁰ isheterocycle optionally substituted with R¹¹ and R¹¹ is alkyl.Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from alkyl and —C(O)R¹⁰ wherein R¹⁰ iscycloalkyl. Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from alkyl and —C(O)R¹⁰ wherein R¹⁰ iscycloalkyl optionally substituted with R¹¹ and R¹¹ is cyano.Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from alkyl and —C(O)R¹⁰ wherein R¹⁰ iscycloalkyl optionally substituted with R¹¹ and R¹¹ is alkyl.Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from alkyl and —C(O)R¹⁰ wherein R¹⁰ iscycloalkyl optionally substituted with R¹¹ and R¹¹ is haloalkyl.Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from alkyl and —C(O)R¹⁰ wherein R¹⁰ is alkyloptionally substituted with R¹¹ and R¹¹ is selected from hydrogen,hydroxyl, and cyano. Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from alkyl and —C(O)R¹⁰ wherein R¹⁰ ishaloalkyl. Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from alkyl and —C(O)R¹⁰ wherein R¹⁰ is alkyloptionally substituted with R¹¹ and R¹¹ is OR⁸. Non-limiting examples ofthis embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with R⁹. In a further embodiment, R⁹ is —C(O)R¹⁰ wherein R¹⁰is heteroaryl or aryl optionally substituted with R¹¹ and R¹¹ isselected from hydrogen and alkyl. Non-limiting examples of thisembodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with R⁹. In a further embodiment, R⁹ is —C(O)NR²R¹⁰ or—C(O)OR¹⁰ wherein R¹⁰ is alkyl. Non-limiting examples of this embodimentinclude:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from alkyl and —CH₂R¹⁰ wherein R¹⁰ iscycloalkyl optionally substituted with R¹¹ and R¹¹ is alkyl.Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from alkyl and —CH₂R¹⁰ wherein R¹⁰ iscycloalkyl optionally substituted with R¹¹ and R¹¹ is selected fromhaloalkyl or cyano. Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from alkyl and —CH₂R¹⁰ wherein R¹⁰ iscycloalkyl optionally substituted with R¹¹ and R¹¹ is OR⁸. Non-limitingexamples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from alkyl and —CH₂R¹⁰ wherein R¹⁰ is alkyloptionally substituted with R¹¹ and R¹¹ is selected from hydrogen,cyano, and OR⁸. Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with R⁹. In a further embodiment, R⁹ is R¹⁰ and R¹⁰ iscycloalkyl. Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroarylsubstituted with R⁷ and substituted with R⁶ wherein R⁶ is heterocycleoptionally substituted with 1 or 2 groups selected from R⁹. In a furtherembodiment, R⁹ is selected from alkyl and —C(O)R¹⁰ and R¹⁰ is cycloalkyloptionally substituted with R¹¹ and R¹¹ is alkyl. A non-limiting exampleof this embodiment includes:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is cycloalkyl. A non-limitingexample of this embodiment includes:

In certain embodiments, R¹ is —C(O)R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle. In a furtherembodiment, R⁶ is optionally substituted with R⁹ and R⁹ is —C(O)OR¹⁰wherein R¹⁰ is alkyl. A non-limiting example of this embodimentincludes:

In certain embodiments, R¹ is —CH(CH₃)R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle. In a furtherembodiment, R⁶ is optionally substituted with R⁹ and R⁹ is —C(O)OR¹⁰ or—C(O)R¹⁰ wherein R¹⁰ is alkyl or cycloalkyl optionally substituted withR¹¹ and R¹¹ is selected from alkyl and hydrogen. Non-limiting examplesof this embodiment include:

In certain embodiments, R¹ is —CH(NH₂)R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle. In a furtherembodiment, R⁶ is optionally substituted with R⁹ and R⁹ is —C(O)OR¹⁰ or—C(O)R¹⁰ wherein R¹⁰ is alkyl or cycloalkyl optionally substituted withR¹¹ and R¹¹ is selected from alkyl and hydrogen. Non-limiting examplesof this embodiment include:

In certain embodiments, R¹ is SR⁴, —S(O)R⁴, or —S(O)₂R⁴ wherein R⁴ isheteroaryl optionally substituted with R⁶ and R⁶ is heterocycleoptionally substituted with R⁹. In a further embodiment, R⁹ is —C(O)R¹⁰wherein R¹⁰ is cycloalkyl optionally substituted with R¹¹ and R¹¹ isalkyl. Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is cycloalkyl optionallysubstituted with R⁹. In a further embodiment, R⁹ is selected from —OR¹⁰wherein R¹⁰ is alkyl optionally substituted with R¹¹ and R¹¹ is aryl. Anon-limiting example of this embodiment includes:

In certain embodiments, R¹ is —(CR³R^(3′))—R⁴ wherein R³ and R^(3′) arebrought together with the carbon to which they are attached to form a3-membered cycloalkyl ring and R⁴ is heteroaryl optionally substitutedwith R⁶ wherein R⁶ is heterocycle optionally substituted with R⁹. In afurther embodiment, R⁹ is —C(O)R¹⁰ or —CH₂R¹⁰ wherein R¹⁰ is cycloalkyloptionally substituted with R¹¹ and R¹¹ is alkyl. Non-limiting examplesof this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is aryl substitutedwith R⁶ and R⁶ is alkyl optionally substituted with R⁹. In a furtherembodiment, R⁹ is R¹⁰ and R¹⁰ is heterocycle optionally substituted withR¹¹ wherein R¹¹ is —C(O)OR⁸, —C(O)R⁸, or —SO₂R⁸ and R⁸ is alkyl,cycloalkyl, haloalkyl, or aryl. Non-limiting examples of this embodimentinclude:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is aryl substitutedwith R⁶ and R⁶ is alkyl optionally substituted with R⁹. In a furtherembodiment, R⁹ is R¹⁰ and R¹⁰ is heterocycle or heteroaryl. Non-limitingexamples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is aryl substitutedwith R⁶ and R⁶ is alkyl optionally substituted with R⁹. In a furtherembodiment, R⁹ is R¹⁰ and R¹⁰ is heterocycle or heteroaryl optionallysubstituted with R¹¹ wherein R¹¹ is selected from hydrogen, alkyl orhaloalkyl. In one embodiment, two R¹¹ groups on the same carbon arebrought together to form an oxo group. Non-limiting examples of thisembodiment include:

In certain embodiments, R¹ is —CH₂—R⁴ wherein R⁴ is aryl optionallysubstituted with R⁶ and R⁶ is alkyl optionally substituted with R⁹. In afurther embodiment, R⁹ is R¹⁰ wherein R¹⁰ is heterocycle optionallysubstituted with R¹¹ and R¹¹ is —CH₂aryl optionally substituted withhalogen. Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —CH₂—R⁴ wherein R⁴ is aryl optionallysubstituted with R⁶ and R⁶ is alkyl optionally substituted with R⁹. In afurther embodiment, R⁹ is R¹⁰ wherein R¹⁰ is heterocycle optionallysubstituted with R¹¹ and R¹¹ is aryl optionally substituted withhalogen. A non-limiting example of this embodiment includes:

In certain embodiments, R¹ is —CH₂—R⁴ wherein R⁴ is aryl optionallysubstituted with R⁶ and R⁶ is heterocycle optionally substituted withR⁹. In a further embodiment, R⁹ is —CH₂R¹⁰ or —C(O)R¹⁰ wherein R¹⁰ iscycloalkyl optionally substituted with R¹¹ and R¹¹ is hydrogen or alkyl.Non-limiting examples of this embodiment include:

In certain embodiments, R¹ is —(CH₂)—R⁴ wherein R⁴ is heteroaryloptionally substituted with R⁶ and R⁶ is heterocycle optionallysubstituted with R⁹. In a further embodiment, R⁹ is selected from R¹⁰wherein R¹⁰ is heteroaryl optionally substituted with R¹¹ groupsselected from halogen and hydrogen. Non-limiting examples of thisembodiment include:

In certain embodiments, R¹ is selected from

Non-Limiting Embodiments of R⁴

In one embodiment of Formula I, R⁴ is selected from:

In one embodiment of Formula I, R⁴ is selected from:

In one embodiment of Formula I, R⁴ is selected from:

In one embodiment of Formula I, R⁴ is selected from:

In one embodiment of Formula I, R⁴ is selected from:

In one embodiment of Formula I, R⁴ is selected from:

In one embodiment of Formula I, R⁴ is selected from:

In one embodiment of Formula I, R⁴ is selected from:

In one embodiment of Formula I, R⁴ is selected from:

In one embodiment of Formula I, R⁴ is selected from:

In one embodiment of Formula I, R⁴ is selected from:

In one embodiment of Formula I, R⁴ is selected from:

In certain embodiments R⁴ is selected from:

In one embodiment, a compound of Formula I is selected from:

In one embodiment, a compound of Formula I is selected from:

In one embodiment, a compound of Formula I is selected from:

In one embodiment, a compound of Formula I is selected from:

In one embodiment, a compound of Formula I is selected from:

In one embodiment, a compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, a compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, a compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

In one embodiment, the compound of Formula I is selected from:

Non-Limiting Embodiments of R⁶

In one embodiment of Formula I, R⁶ is selected from:

In one embodiment of Formula L R⁶ is selected from:

In one embodiment of Formula I, R⁶ is selected from:

In one embodiment of Formula I, R⁶ is selected from:

In one embodiment of Formula I, R⁶ is selected from:

In one embodiment of Formula I, R⁶ is selected from:

In certain embodiments R⁶ is selected from:

Non-Limiting Embodiments of R⁹

In one embodiment, R⁹ is selected from:

In one embodiment, R⁹ is selected from:

In one embodiment, R⁹ is selected from:

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In one embodiment, R⁹ is

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In one embodiment, R⁹ is selected from:

Non-Limiting Embodiments of R¹⁰

Non-limiting examples of —C(O)R¹⁰ include:

Non-limiting examples of —CH₂R¹⁰ include:

Non-limiting examples of R¹⁰ include:

Non-Limiting Examples of Compounds of Formula I or Formula II

Representative examples of compounds of Formula I or Formula II include:

Additional representative examples of compounds of Formula I or FormulaII include:

Additional representative examples of compounds of Formula I or IIinclude:

In certain embodiments the compound of the present invention is selectedfrom:

In one embodiment the compound of the present invention is:

or a pharmaceutically acceptable salt thereof.

Non-limiting Isotopic Embodiments

In one embodiment the compound is isotopically labeled. In oneembodiment at least one R group independently selected from R¹, R², R³,R³′, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R²⁰, R²¹, R²², R²³, R²⁴,R²⁵, R²⁶, R²⁸, or R⁴⁰ is isotopically labeled with 1, 2, or moreisotopes as allowed by valence. In one embodiment the isotopic label isdeuterium. In one embodiment, at least one deuterium is placed on anatom that has a bond which is broken during metabolism of the compoundin vivo, or is one, two or three atoms remote form the metabolized bond(e.g., which may be referred to as an α, β or γ, or primary, secondaryor tertiary isotope effect). In another embodiment the isotopic label is¹³C. In another embodiment the isotopic label is ¹⁸F.

In certain embodiments the compound of the present invention is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In certain embodiments the compound of the present invention is selectedfrom:

or a pharmaceutically acceptable salt thereof.

In any of the above structures where there are two deuterium on amethylene the same molecule with one deuterium at that position isenvisioned. In any of the above structures where there are threedeuterium on a methyl the same molecule with one or two deuterium atthat position is envisioned.

Additional Embodiments

1. In certain embodiments a compound is provided of Formula I or FormulaII

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof;

wherein:

X¹ and X² are independently selected from CH and N;

X³ is selected from bond, NR², C(R³R^(3′)), O, C(O), C(S), S, S(O), andS(O)₂;

R¹ is selected from hydrogen, halogen, cyano, nitro, alkyl, haloalkyl,—NR²R^(2′), —OR², —NR²R⁴, —NR²R⁵, —OR⁵, —(CR³R^(3′))—R⁴,—(CR³R^(3′))—R⁵, —(CR³R^(3′))—NR²R⁴, —(CR³R^(3′))—NR²R⁵,—(CR³R^(3′))—OR⁴, —(CR³R^(3′))—OR⁵, —C(O)R⁴, —SR⁴, —SR⁵, —S(O)R⁴, and—S(O)₂R⁴;

R² and R^(2′) are independently selected at each occurrence fromhydrogen, alkyl, haloalkyl, cycloalkyl, heterocycle, aryl, heteroaryl,—C(O)R⁸, —C(O)OR⁸, —C(O)—NR⁸R^(8′), —S(O)R⁸, —SO₂R⁸, —SO₂—OR⁸, and—SO₂—NR⁸R^(8′);

R³ is selected from hydrogen, halogen, alkyl, haloalkyl, —OR⁸, andNR⁸R^(8′);

R^(3′) is selected from hydrogen, halogen, alkyl, and haloalkyl;

or R³ and R^(3′) can be brought together with the carbon to which theyare attached to form a 3- to 6-membered cycloalkyl ring;

R⁴ is selected from cycloalkyl, heterocycle, aryl, and heteroaryl,wherein each R⁴ is optionally substituted with one group selected fromR⁶, and wherein each R⁴ is also optionally substituted with 1, 2, 3, or4 groups independently selected from R⁷;

R⁵ is —C(O)R⁶;

R⁶ is selected from alkyl, cycloalkyl, heterocycle, aryl, andheteroaryl, wherein each R⁶ is optionally substituted with 1, 2, 3, or 4groups independently selected from R⁹;

or R⁶ is selected from alkyl, cycloalkyl, heterocycle, aryl, heteroaryl,—CO-alkyl, —CO-cycloalkyl, —CO-heterocycle, —CO-aryl, —CO-heteroaryl,—O-alkyl, —O-cycloalkyl, —O-heterocycle, —O-aryl, —O-heteroaryl,—NR²-alkyl, —NR²-cycloalkyl, —NR²-heterocycle, —NR²-aryl, and—NR²-heteroaryl, wherein each R⁶ is optionally substituted with 1, 2, 3,or 4 groups independently selected from R⁹;

R⁷ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, aryl, heteroaryl, —OR⁸, —NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,—C(O)—NR⁸R^(8′), —OC(O)R⁸, —NR²—C(O)R⁸, —S(O)R⁸, —SO₂R⁸, —SO₂—OR⁸, and—SO₂—NR⁸R^(8′);

or two R⁷ on the same carbon may be brought together to form an oxogroup;

R⁸ and R^(8′) are independently selected at each occurrence fromhydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle,aryl, and heteroaryl;

R⁹ is independently selected at each occurrence from hydrogen, halogen,cyano, nitro, R¹⁰, —CH₂R¹⁰, —OR¹⁰, —NR²R¹⁰, —C(O)R¹⁰, —C(O)CH₂R¹⁰,—C(O)CH₂OR¹⁰, —C(O)CH₂NR²R¹⁰, —OC(O)R¹⁰, —NR²—C(O)R¹⁰, —C(O)OR¹⁰,—C(O)NR²R¹⁰, —S(O)R¹⁰, —SO₂R¹⁰, SO₂CH₂R¹⁰, —SO₂CH₂OR¹⁰, —SO₂CH₂NR²R¹⁰,—NR²SO₂R¹⁰, —SO₂—OR¹⁰, and —SO₂—NR²R¹⁰;

R¹⁰ is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, aryl, and heteroaryl, wherein each R¹⁰ is optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R¹¹;and

R¹¹ is selected from: hydrogen; halogen; hydroxyl; cyano; nitro; alkyl;haloalkyl; alkenyl optionally substituted with an aryl or heteroarylgroup; alkynyl optionally substituted with an aryl or heteroaryl group;cycloalkyl; heterocycle; aryl optionally substituted with 1, 2, 3, or 4halogen, alkyl, or —OR⁸ groups; heteroaryl optionally substituted with1, 2, 3, or 4 halogen, alkyl, or —OR⁸ groups; —CH₂aryl optionallysubstituted with 1, 2, 3, or 4 halogen, alkyl, or —OR⁸ groups;—CH₂heteroaryl optionally substituted with 1, 2, 3, or 4 halogen, alkyl,or —OR⁸ groups; —OR⁸; —NR⁸R^(8′); —C(O)R⁸; —C(O)OR⁸; —C(O)—NR⁸R^(8′);—C(O)CH₂R⁸; —C(O)CH₂OR⁸; —C(O)CH₂—NR⁸R^(8′); —OC(O)R⁸; —NR²—C(O)R⁸;—CH₂—OC(O)R⁸; —CH₂—NR²—C(O)R⁸; —S(O)R⁸; —SO₂R⁸; —SO₂—OR⁸; and—SO₂—NR⁸R^(8′);

or two R¹¹ groups on the same carbon may be brought together to form anoxo group.

or R¹¹ is independently selected at each occurrence from: halogen;hydroxyl; cyano; nitro;

alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl; heterocycle; aryl;heteroaryl; —CH₂aryl; —CH₂heteroaryl; —OR⁸; —NR⁸R^(8′); —C(O)R⁸;—C(O)OR⁸; —C(O)—NR⁸R^(8′); —C(O)CH₂R⁸; —C(O)CH₂OR⁸; —C(O)CH₂—NR⁸R^(8′);—OC(O)R⁸; —NR²—C(O)R⁸; —CH₂—OC(O)R⁸; —CH₂—NR²—C(O)R⁸; —S(O)R⁸; —SO₂R⁸;—SO₂—OR⁸; oxo, and —SO₂—NR⁸R^(8′); each of which R¹¹ groups isoptionally substituted with 1, 2, 3, or 4, groups independently selectedfrom R¹²;

R¹² is independently selected at each occurrence from: halogen;hydroxyl; cyano; nitro; alkyl; haloalkyl; alkenyl; alkynyl; cycloalkyl;heterocycle; aryl; heteroaryl; —CH₂aryl; —CH₂heteroaryl; —OR⁸;—NR⁸R^(8′); —C(O)R⁸; —C(O)OR⁸; —C(O)—NR⁸R^(8′); —C(O)CH₂R⁸; —C(O)CH₂OR⁸;—C(O)CH₂—NR⁸R^(8′); —OC(O)R⁸; —NR²—C(O)R⁸; —CH₂—OC(O)R⁸;—CH₂—NR²—C(O)R⁸; —S(O)R⁸; —SO₂R⁸; —SO₂—OR⁸; oxo; and —SO₂—NR⁸R^(8′);

R²⁰, R²¹, R²², R²³, and R²⁴ are independently at each occurrenceselected from the group consisting of a bond, alkyl, —C(O)—, —C(O)O—,—OC(O)—, —SO₂—, —S(O)—, —C(S)—, —C(O)NR²—, —NR²C(O)—, —O—, —S—, —NR²—,—P(O)(R²⁸)—, —P(O)—, alkene, alkyne, haloalkyl, aryl, heterocycle,heteroaryl, bicycle, and carbocycle; each of which is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁴⁰; and wherein R²⁰, R²¹, R²², R²³, and R²⁴ cannot be selected in sucha way that

-   -   i. —C(O)—, —C(O)O—, —OC(O)—, —SO₂—, —S(O)—, —P(O)(R²⁸)—, —P(O)—,        and —C(S)— moieties are adjacent to each other; or    -   ii. —O—, —S—, or —NR²— moieties are adjacent to each other; or    -   iii. moieties are otherwise selected in an order that an        unstable molecule results (as defined as producing a molecule        that has a shelf life at ambient temperature of less than about        four months (or alternatively less than about six or five        months) due to decomposition caused by the selection and order        of the moieties R²⁰, R²¹, R²², R²³, and R²⁴);

R²⁵ is selected from hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl,alkoxy, azide, amino, cyano, —OR², —NR²R^(2′), —NR²SO₂R²⁸, —OSO₂R²⁸,—SO₂R²⁸, haloalkyl, aryl, heteroaryl, heterocycle, bicycle, andcycloalkyl; each of which R²⁵ groups is optionally substituted with 1,2, 3, or 4 groups independently selected from R¹²;

R²⁸ independently selected at each occurrence from hydrogen, —NR²R^(2′),—OR², —SR², alkyl haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle,aryl, and heteroaryl;

R⁴⁰ is independently at each occurrence selected from the groupconsisting of hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl,alkoxy, azide, amino, cyano, —NR²R^(2′), —NR²SO₂R²⁸, —OSO₂R²⁸, —SO₂R²⁸,haloalkyl, aryl, heteroaryl, heterocycle, oxo, and cycloalkyl; each ofwhich R⁴⁰ groups is optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R¹².

2. The compound of embodiment 1 of Formula:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof.

3. The compound of embodiment 2, wherein:

R⁶ is selected from alkyl, cycloalkyl, heterocycle, aryl, andheteroaryl, wherein each R⁶ is optionally substituted with 1, 2, 3, or 4groups independently selected from R⁹; and

R¹¹ is selected from: hydrogen; halogen; hydroxyl; cyano; nitro; alkyl;haloalkyl; alkenyl optionally substituted with an aryl or heteroarylgroup; alkynyl optionally substituted with an aryl or heteroaryl group;cycloalkyl; heterocycle; aryl optionally substituted with 1, 2, 3, or 4halogen, alkyl, or —OR⁸ groups; heteroaryl optionally substituted with1, 2, 3, or 4 halogen, alkyl, or —OR⁸ groups; —CH₂aryl optionallysubstituted with 1, 2, 3, or 4 halogen, alkyl, or —OR⁸ groups;—CH₂heteroaryl optionally substituted with 1, 2, 3, or 4 halogen, alkyl,or —OR⁸ groups; —OR⁸; —NR⁸R^(8′); —C(O)R⁸; —C(O)OR⁸; —C(O)—NR⁸R^(8′);—C(O)CH₂R⁸; —C(O)CH₂OR⁸; —C(O)CH₂—NR⁸R^(8′); —OC(O)R⁸; —NR²—C(O)R⁸;—CH₂—OC(O)R⁸; —CH₂—NR²—C(O)R⁸; —S(O)R⁸; —SO₂R⁸; —SO₂—OR⁸; and—SO₂—NR⁸R^(8′);

or two R¹¹ groups on the same carbon may be brought together to form anoxo group.

4. The compound of embodiment 1 or embodiment 2, wherein R¹² is selectedfrom halogen, alkyl, and haloalkyl.

5. The compound of embodiment 1 or embodiment 2, wherein R¹² is selectedfrom hydroxyl, cyano, nitro, alkenyl, alkynyl, cycloalkyl, heterocycle,aryl, and heteroaryl.

6. The compound of embodiment 1 or embodiment 2, wherein R¹² is selectedfrom —CH₂aryl; —CH₂heteroaryl; —OR⁸; —NR⁸R^(8′); —C(O)R⁸; —C(O)OR⁸;—C(O)—NR⁸R^(8′); —C(O)CH₂R⁸; —C(O)CH₂OR⁸; —C(O)CH₂—NR⁸R^(8′); —OC(O)R⁸;—NR²—C(O)R⁸; —CH₂—OC(O)R⁸; —CH₂—NR²—C(O)R⁸; —S(O)R⁸; —SO₂R⁸; —SO₂—OR⁸;oxo; and —SO₂—NR⁸R^(8′).

7. The compound of embodiment 1 or 2, wherein one R¹² substituent ishalogen.

8. The compound of embodiment 1 or 2, wherein two R¹² substituents arehalogen.

9. The compound of embodiment 1 or 2, wherein one R¹² substituent isalkyl.

10. The compound of embodiment 1 or 2, wherein two R¹² substituents arealkyl.

11. The compound of embodiment 1 or 2, wherein one R¹² substituent ishaloalkyl.

12. The compound of embodiment 1 or 2, wherein one R¹² substituent iscycloalkyl.

13. The compound of any one of embodiments 4-12, wherein R¹¹ is alkyloptionally substituted with 1, 2, 3, or 4 substituents selected fromR¹².

14. The compound of any one of embodiments 4-12, wherein R¹¹ iscycloalkyl optionally substituted with 1, 2, 3, or 4 substituentsselected from R¹².

15. The compound of any one of embodiments 4-12, wherein R¹¹ isheterocycle optionally substituted with 1, 2, 3, or 4 substituentsselected from R^(u).

16. The compound of any one of embodiments 4-12, wherein R¹¹ is aryloptionally substituted with 1, 2, 3, or 4 substituents selected fromR^(u).

17. The compound of any one of embodiments 4-12, wherein R¹¹ isheteroaryl optionally substituted with 1, 2, 3, or 4 substituentsselected from R^(u).

18. The compound of any one of embodiments 1-12, wherein R¹¹ is alkyl.

19. The compound of any one of embodiments 1-12, wherein R¹¹ is cyano.

20. The compound of any one of embodiments 1-12, wherein R¹¹ ishaloalkyl.

21. The compound of any one of embodiments 1-12, wherein R¹¹ ishydrogen.

22. The compound of any one of embodiments 1-12, wherein R¹¹ ishydroxyl.

23. The compound of any one of embodiments 1-12, wherein R¹¹ is OR⁸.

24. The compound of any one of embodiments 1-12, wherein R¹¹ is aryl.

25. The compound of any one of embodiments 1-12, wherein R¹¹ isheteroaryl.

26. The compound of any one of embodiments 1-12, wherein R¹¹ is—C(O)OR⁸, —C(O)R⁸, or —SO₂R⁸.

27. The compound of any one of embodiments 1-12, wherein R¹¹ is—CH₂aryl.

28. The compound of any one of embodiments 1-27, wherein R¹ is —NR²R⁴.

29. The compound of any one of embodiments 1-27, wherein R¹ is —OR⁴.

30. The compound of any one of embodiments 1-27, wherein R¹ is —C(O)R⁴.

31. The compound of any one of embodiments 1-27, wherein R¹ is —SR⁴.

32. The compound of any one of embodiments 1-27, wherein R¹ is —S(O)R⁴.

33. The compound of any one of embodiments 1-27, wherein R¹ is and—S(O)₂R⁴.

34. The compound of any one of embodiments 1-27, wherein the compound isof Formula:

or a pharmaceutically acceptable salt thereof.

35. The compound of any one of embodiments 1-27, wherein the compound isof Formula:

or a pharmaceutically acceptable salt thereof.

36. The compound of any one of embodiments 1-27, wherein the compound isof Formula:

or a pharmaceutically acceptable salt thereof.

37. The compound of any one of embodiments 1-27, wherein the compound isof Formula:

or a pharmaceutically acceptable salt thereof.

38. The compound of any one of embodiments 1-27, wherein R¹ is—(CR³R^(3′))—R⁵.

39. The compound of embodiment 37 or 38, wherein R³ is hydrogen.

40. The compound of embodiment 37 or 38, wherein R³ is NR⁸R^(8′).

41. The compound of embodiment 37 or 38, wherein R³ is alkyl.

42. The compound of any one of embodiments 37-41, wherein R^(3′) ishydrogen.

43. The compound of any one of embodiments 1-27, wherein R¹ is —NR²R⁵.

44. The compound of any one of embodiments 1-27, wherein R¹ is —OR⁵.

45. The compound of any one of embodiments 38-44, wherein R⁵ is—C(O)alkyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R⁹.

46. The compound of any one of embodiments 38-44, wherein R⁵ is—C(O)heterocycle optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R⁹.

47. The compound of any one of embodiments 38-44, wherein R⁵ is—C(O)aryl optionally substituted with 1, 2, 3, or 4 groups independentlyselected from R⁹.

48. The compound of any one of embodiments 38-44, wherein R⁵ is—C(O)heteroaryl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R⁹.

49. The compound of any one of embodiments 1-48, wherein the compound isof Formula:

or a pharmaceutically acceptable salt thereof.

50. The compound of any one of embodiments 1-48, wherein the compound isof Formula:

or a pharmaceutically acceptable salt thereof.

51. The compound of any one of embodiments 1-48, wherein the compound isof Formula:

or a pharmaceutically acceptable salt thereof.

52. The compound of any one of embodiments 49-51, wherein R⁴ iscycloalkyl substituted with one group selected from R⁶, and optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R⁷.

53. The compound of any one of embodiments 49-51, wherein R⁴ isheterocycle substituted with one group selected from R⁶, and optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R⁷.

54. The compound of any one of embodiments 49-51, wherein R⁴ is arylsubstituted with one group selected from R⁶, and optionally substitutedwith 1, 2, 3, or 4 groups independently selected from R⁷.

55. The compound of any one of embodiments 49-51, wherein R⁴ isheteroaryl substituted with one group selected from R⁶, and optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R⁷.

56. The compound of any one of embodiments 49-51, wherein R⁴ is

57. The compound of any one of embodiments 49-51, wherein R⁴ is

58. The compound of any one of embodiments 49-51, wherein R⁴ is

59. The compound of any one of embodiments 49-51, wherein R⁴ is

60. The compound of any one of embodiments 49-51, wherein R⁴ is

61. The compound of any one of embodiments 1-60, wherein R⁷ is selectedfrom hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl,alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, —OR⁸, and—NR⁸R^(8′).

62. The compound of any one of embodiments 1-60, wherein R⁷ is selectedfrom hydrogen, halogen, alkyl, haloalkyl, —C(O)R⁸, —C(O)OR⁸,—C(O)—NR⁸R^(8′), —OC(O)R⁸, —NR²—C(O)R⁸, —S(O)R⁸, —SO₂R⁸, —SO₂—OR⁸, and—SO₂—NR⁸R^(8′).

63. The compound of any one of embodiments 1-60, wherein one R⁷ ishydrogen.

64. The compound of any one of embodiments 1-60, wherein two R⁷s arehydrogen.

65. The compound of any one of embodiments 1-60, wherein three R⁷s arehydrogen.

66. The compound of any one of embodiments 1-65, wherein one R⁷ ishalogen.

67. The compound of any one of embodiments 1-64, wherein two R⁷s arehalogen.

68. The compound of any one of embodiments 1-65, wherein one R⁷ isalkyl.

69. The compound of any one of embodiments 1-64, wherein two R⁷s arealkyl.

70. The compound of any one of embodiments 1-65, wherein one R⁷ ishaloalkyl.

71. The compound of any one of embodiments 1-64, wherein two R⁷s arehaloalkyl.

72. The compound of any one of embodiments 1-71, wherein R⁶ is selectedfrom:

73. The compound of any one of embodiments 1-71, wherein R⁶ is selectedfrom:

74. The compound of any one of embodiments 1-71, wherein R⁶ is selectedfrom:

75. The compound of any one of embodiments 1-71, wherein R⁶ is alkyloptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R⁹.

76. The compound of any one of embodiments 1-71, wherein R⁶ iscycloalkyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R⁹.

77. The compound of any one of embodiments 1-71, wherein R⁶ isheterocycle optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R⁹.

78. The compound of any one of embodiments 1-71, wherein R⁶ is aryloptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R⁹.

79. The compound of any one of embodiments 1-71, wherein R⁶ isheteroaryl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R⁹.

80. The compound of any one of embodiments 75-79, wherein R⁶ is notsubstituted.

81. The compound of any one of embodiments 75-79, wherein R⁶ issubstituted with 1 group selected from R⁹.

82. The compound of any one of embodiments 75-79, wherein R⁶ issubstituted with 2 groups independently selected from R⁹.

83. The compound of any one of embodiments 75-79, wherein R⁶ issubstituted with 3 groups independently selected from R⁹.

84. The compound of any one of embodiments 75-79, wherein R⁶ issubstituted with 4 groups independently selected from R⁹.

85. The compound of any one of embodiments 1-84, wherein R⁹ is selectedfrom hydrogen, halogen, alkyl, haloalkyl, cyano, and nitro.

86. The compound of any one of embodiments 1-84, wherein R⁹ is selectedfrom R⁹.

87. The compound of any one of embodiments 1-84, wherein R⁹ is selectedfrom —CH₂R¹⁰, —OR¹⁰, —NR²R¹⁰, —C(O)R¹⁰, —C(O)CH₂R¹⁰, —C(O)CH₂OR¹⁰,—C(O)CH₂NR²R¹⁰, —OC(O)R¹⁰, —NR²—C(O)R¹⁰, —C(O)OR¹⁰, —C(O)NR²R¹⁰,—S(O)R¹⁰, —SO₂R¹⁰, SO₂CH₂R¹⁰, —SO₂CH₂OR¹⁰, —SO₂CH₂NR²R¹⁰, —NR²SO₂R¹⁰,—SO₂—OR¹⁰, and —SO₂—NR²R¹⁰.

88. The compound of embodiment 86 or 87, wherein R¹⁰ is alkyl optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R¹¹.

89. The compound of embodiment 86 or 87, wherein R¹⁰ is haloalkyloptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R¹¹.

90. The compound of embodiment 86 or 87, wherein R¹⁰ is alkenyloptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R¹¹.

91. The compound of embodiment 86 or 87, wherein R¹⁰ is alkynyloptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R¹¹.

92. The compound of embodiment 86 or 87, wherein R¹⁰ is cycloalkyloptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R¹¹.

93. The compound of embodiment 86 or 87, wherein R¹⁰ heterocycleoptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R¹¹.

94. The compound of embodiment 86 or 87, wherein R¹⁰ is aryl optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R¹¹.

95. The compound of embodiment 86 or 87, wherein R¹⁰ is heteroaryloptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R¹¹.

96. The compound of any one of embodiments 88-95, wherein R¹⁰ is notsubstituted.

97. The compound of any one of embodiments 88-95, wherein R¹⁰ issubstituted with 1 group selected from R¹¹.

98. The compound of any one of embodiments 88-95, wherein R¹⁰ issubstituted with 2 groups independently selected from R¹¹.

99. The compound of any one of embodiments 88-95, wherein R¹⁰ issubstituted with 3 groups independently selected from R¹¹.

100. The compound of any one of embodiments 88-95, wherein R¹⁰ issubstituted with 4 groups independently selected from R¹¹.

101. The compound of any one of embodiments 1-100, wherein R², R⁸, andR^(8′) are hydrogen.

102. The compound of any one of embodiments 1-100, wherein R², R⁸, andR^(8′) are alkyl.

103. The compound of any one of embodiments 1-71, wherein R⁶ is selectedfrom:

104. The compound of any one of embodiments 1-71, wherein R⁶ is selectedfrom:

105. The compound of any one of embodiments 1-71, wherein R⁶ is selectedfrom:

106. The compound of embodiment 1, wherein the compound is of Formula:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof.

107. The compound of embodiment 106, wherein the compound is of Formula:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof.

108. The compound of embodiment 106, wherein the compound is of Formula:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof.

109. The compound of embodiment 106, wherein the compound is of Formula:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof.

110. The compound of any one of embodiments 106-109, wherein X³ is bond.

111. The compound of any one of embodiments 106-109, wherein X³ isC(R³R^(3′)).

112. The compound of any one of embodiments 106-109, wherein X³ is C(O).

113. The compound of any one of embodiments 106-109, wherein X³ is C(S).

114. The compound of any one of embodiments 106-109, wherein X³ is S(O).

115. The compound of any one of embodiments 106-109, wherein X³ is S(O)₂

116. The compound of any one of embodiments 106-109, wherein X³ is NR².

117. The compound of any one of embodiments 106-109, wherein X³ is O.

118. The compound of any one of embodiments 106-109, wherein X³ is NR².

119. The compound of any one of embodiments 106-109, wherein X³ is O.

120. The compound of any one of embodiments 106-109, wherein X³ is S.

121. The compound of any one of embodiments 106-120, wherein R²⁰ isbond.

122. The compound of any one of embodiments 106-120, wherein R²⁰ isalkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

123. The compound of any one of embodiments 106-120, wherein R²⁰ isalkene or alkyne optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

124. The compound of any one of embodiments 106-120, wherein R²⁰ ishaloalkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

125. The compound of any one of embodiments 106-120, wherein R²⁰ is aryloptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁴⁰.

126. The compound of any one of embodiments 106-120, wherein R²⁰ isheteroaryl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

127. The compound of any one of embodiments 106-120, wherein R²⁰ isheterocycle optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

128. The compound of any one of embodiments 106-120, wherein R²⁰ isbicycle optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

129. The compound of any one of embodiments 106-115, wherein R²⁰ is —O—.

130. The compound of any one of embodiments 106-115, wherein R²⁰ is —S—.

131. The compound of any one of embodiments 106-115, wherein R²⁰ is—NR²—.

132. The compound of any one of embodiments 106-111, wherein R²⁰ is—C(O)—, —C(O)O—, —OC(O)—, —SO₂—, —S(O)—, —C(S)—, —C(O)NR²—, —P(O)(R²⁸)—,or —P(O)—.

133. The compound of any one of embodiments 106-132, wherein R²¹ isbond.

134. The compound of any one of embodiments 106-132, wherein R²¹ isalkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

135. The compound of any one of embodiments 106-132, wherein R²¹ isalkene or alkyne optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

136. The compound of any one of embodiments 106-132, wherein R²¹ ishaloalkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

137. The compound of any one of embodiments 106-132, wherein R²¹ is aryloptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁴⁰.

138. The compound of any one of embodiments 106-132, wherein R²¹ isheteroaryl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

139. The compound of any one of embodiments 106-132, wherein R²¹ isheterocycle optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

140. The compound of any one of embodiments 106-132, wherein R²¹ isbicycle optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

141. The compound of any one of embodiments 106-128, wherein R²¹ is —O—.

142. The compound of any one of embodiments 106-128, wherein R²¹ is —S—.

143. The compound of any one of embodiments 106-128, wherein R²¹ is—NR²—.

144. The compound of any one of embodiments 106-131, wherein R²¹ is—C(O)—, —C(O)O—, —OC(O)—, —SO₂—, —S(O)—, —C(O)NR²—, —P(O)(R²⁸)—, or—P(O)—.

145. The compound of any one of embodiments 106-144, wherein R²² isbond.

146. The compound of any one of embodiments 106-144, wherein R²² isalkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

147. The compound of any one of embodiments 106-144, wherein R²² isalkene or alkyne optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

148. The compound of any one of embodiments 106-144, wherein R²² ishaloalkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

149. The compound of any one of embodiments 106-144, wherein R²² is aryloptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁴⁰.

150. The compound of any one of embodiments 106-144, wherein R²² isheteroaryl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

151. The compound of any one of embodiments 106-144, wherein R²² isheterocycle optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

152. The compound of any one of embodiments 106-144, wherein R²² isbicycle optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

153. The compound of any one of embodiments 106-143, wherein R²² is—C(O)—, —C(O)O—, —OC(O)—, —SO₂—, —S(O)—, —C(O)NR²—, —P(O)(R²⁸)—, or—P(O)—.

154. The compound of any one of embodiments 106-140, wherein R²² is —O—.

155. The compound of any one of embodiments 106-140, wherein R²² is —S—.

156. The compound of any one of embodiments 106-140, wherein R²² is—NR²—.

157. The compound of any one of embodiments 106-156, wherein R²³ or R²⁴is bond.

158. The compound of any one of embodiments 106-156, wherein R²³ or R²⁴is alkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

159. The compound of any one of embodiments 106-156, wherein R²³ or R²⁴is alkene or alkyne optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁴⁰.

160. The compound of any one of embodiments 106-156, wherein R²³ or R²⁴is haloalkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

161. The compound of any one of embodiments 106-156, wherein R²³ or R²⁴is aryl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

162. The compound of any one of embodiments 106-156, wherein R²³ or R²⁴is heteroaryl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

163. The compound of any one of embodiments 106-156, wherein R²³ or R²⁴is heterocycle optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

164. The compound of any one of embodiments 106-156, wherein R²³ or R²⁴is bicycle optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

165. The compound of any one of embodiments 106-156, wherein R²³ or R²⁴is —C(O)—, —C(O)O—, —OC(O)—, —SO₂—, —S(O)—, —C(S)—, —C(O)NR²—,—P(O)(R²⁸)—, or —P(O)—.

166. The compound of any one of embodiments 106-156, wherein R²³ or R²⁴is —O—.

167. The compound of any one of embodiments 106-156, wherein R²³ or R²⁴is —S—.

168. The compound of any one of embodiments 106-156, wherein R²³ or R²⁴is —NR²—.

169. The compound of any one of embodiments 106-168, wherein R²⁵ ishydrogen.

170. The compound of any one of embodiments 106-168, wherein R²⁵ ishalogen.

171. The compound of any one of embodiments 106-168, wherein R²⁵ isalkyl optionally substituted with 1, 2, 3, or 4 groups independentlyselected from R¹².

172. The compound of any one of embodiments 106-168, wherein R²⁵ isselected from alkene, alkyne, hydroxyl, alkoxy, azide, amino, cyano,—OR², —NR²R^(2′), —NR²SO₂R²⁸, —OSO₂R²⁸, —SO₂R²⁸, haloalkyl, aryl,heteroaryl, heterocycle, bicycle, and cycloalkyl; each of which R²⁵groups is optionally substituted with 1, 2, 3, or 4 groups independentlyselected from R¹²;

173. The compound of anyone one of embodiments 106-172, wherein R⁴⁰ isselected from alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide,amino, cyano, haloalkyl, aryl, heteroaryl, heterocycle, oxo, andcycloalkyl; each of which R⁴⁰ groups is optionally substituted with 1,2, 3, or 4 groups independently selected from R¹².

174. The compound of embodiment 173, wherein R⁴⁰ is not substituted.

175. The compound of embodiment 1, wherein the compound is selectedfrom:

or a pharmaceutically acceptable salt thereof.

176. The compound of embodiment 1, wherein the compound is selected fromTable 2 or a pharmaceutically acceptable salt thereof.

177. The compound of embodiment 1, wherein the compound is of structure:

or a pharmaceutically acceptable salt thereof.

178. The compound of embodiment 1, wherein the compound is of structure:

or a pharmaceutically acceptable salt thereof.

179. The compound of embodiment 1, wherein the compound is of structure:

or a pharmaceutically acceptable salt thereof.

180. The compound of embodiment 1, wherein the compound is of structure:

or a pharmaceutically acceptable salt thereof.

181. The compound of embodiment 1, wherein the compound is of structure:

or a pharmaceutically acceptable salt thereof.

182. In certain embodiments a pharmaceutical composition comprising acompound of any one of embodiments 1-181 or a pharmaceutical saltthereof and a pharmaceutically acceptable excipient is provided.

183. In certain embodiments a method of treating a disorder mediated bycereblon in a human comprising administering an effective dose of acompound of any one of embodiments 1-181 or a pharmaceuticallyacceptable salt or composition thereof to a human in need thereof isprovided.

184. The method of embodiment 183, wherein the disorder is mediated byIkaros or Aiolos.

185. The method of embodiment 183 or 184, wherein the disorder is acancer.

186. The method of embodiment 183 or 184, wherein the disorder is atumor.

187. The method of embodiment 183 or 184, wherein the disorder is animmune, autoimmune, or inflammatory disorder.

188. The method of embodiment 183 or 184, wherein the disorder is ahematological malignancy.

189. The method of embodiment 183 or 184, wherein the disorder ismultiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocyticleukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma.

190. In certain embodiments a compound for use in the manufacture of amedicament to treat a disorder mediated by cereblon in a human whereinthe compound is selected any one of embodiments 1-181 or apharmaceutically acceptable salt or composition thereof is provided.

191. The compound for use of embodiment 190, wherein the disorder ismediated by Ikaros or Aiolos.

192. The compound for use of embodiment 190 or 191, wherein the disorderis a cancer.

193. The compound for use of embodiment 190 or 191, wherein the disorderis a tumor.

194. The compound for use of embodiment 190 or 191, wherein the disorderis an immune, autoimmune, or inflammatory disorder.

195. The compound for use of embodiment 190 or 191, wherein the disorderis a hematological malignancy.

196. The compound for use of embodiment 190 or 191, wherein the disorderis multiple myeloma, leukemia, lymphoblastic leukemia, chroniclymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma.

197. In certain embodiments a use of a compound in the treatment of adisorder mediated by cereblon in a human wherein the compound isselected any one of embodiments 1-181 or a pharmaceutically acceptablesalt or composition thereof is provided.

198. The use of embodiment 197, wherein the disorder is mediated byIkaros or Aiolos.

199. The use of embodiment 197 or 198, wherein the disorder is a cancer.

200. The use of embodiment 197 or 198, wherein the disorder is a tumor.

201. The use of embodiment 197 or 198, wherein the disorder is animmune, autoimmune, or inflammatory disorder.

202. The use of embodiment 197 or 198, wherein the disorder is ahematological malignancy.

203. The use of embodiment 197 or 198, wherein the disorder is multiplemyeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia,Hodgkin's lymphoma, or non-Hodgkin's lymphoma.

III. Methods of Treatment

Any of the compounds described herein can be used in an effective amountto treat a host, including a human, in need thereof, optionally in apharmaceutically acceptable carrier to treat any of the disordersdescribed herein. In certain embodiments, the method comprisesadministering an effective amount of the active compound or its salt asdescribed herein, optionally including a pharmaceutically acceptableexcipient, carrier, or adjuvant (i.e., a pharmaceutically acceptablecomposition), optionally in combination or alternation with anadditional therapeutically active agent or combination of agents.

In one embodiment, the compound of the present invention selectivelydegrades IKZF1 and/or 3 over one or more of IKZF2 and/or 4 and/or 5.

In one embodiment a compound of Formula I is used to treat a disorderdescribed herein.

In one embodiment a compound of Formula II is used to treat a disorderdescribed herein.

In one embodiment a compound of Formula I-a is used to treat a disorderdescribed herein.

In one embodiment a compound of Formula I-b is used to treat a disorderdescribed herein.

In one embodiment a compound of Formula I-c is used to treat a disorderdescribed herein.

In one embodiment a compound of Formula I-d is used to treat a disorderdescribed herein.

In one embodiment a compound of Formula I-e is used to treat a disorderdescribed herein.

In one embodiment a compound of Formula I-f is used to treat a disorderdescribed herein.

In one embodiment a compound of Formula I-g is used to treat a disorderdescribed herein.

In one embodiment the disorder treated by a compound of the presentinvention is an immunomodulatory disorder. In one embodiment thedisorder treated by a compound of the present invention is mediated byangiogenesis. In one embodiment the disorder treated by a compound ofthe present invention is related to the lymphatic system.

In one embodiment a compound of the present invention pharmaceuticalsalt thereof, optionally in a pharmaceutical composition as describedherein is used to degrade Ikaros or Aiolos, which is a mediator of thedisorder affecting the patient, such as a human. The control of proteinlevel afforded by any of the compounds of the present invention providestreatment of a disease state or condition, which is modulated throughIkaros or Aiolos by lowering the level of that protein in the cell,e.g., cell of a patient, or by lowering the level of downstream proteinsin the cell. In certain embodiments, the method comprises administeringan effective amount of the compound as described herein, optionallyincluding a pharmaceutically acceptable excipient, carrier, adjuvant(i.e., a pharmaceutically acceptable composition), optionally incombination or alternation with an additional therapeutically activeagent or combination of agents.

In one embodiment, a compound of the present invention is used to treata disorder including, but not limited to, benign growth, neoplasm,tumor, cancer, abnormal cellular proliferation, immune disorder,inflammatory disorder, graft-versus-host rejection, viral infection,bacterial infection, an amyloid-based proteinopathy, a proteinopathy, ora fibrotic disorder.

The term “disease state” or “condition” when used in connection with anyof the compounds is meant to refer to any disease state or conditionthat is mediated by Ikaros or Aiolos, such as cellular proliferation, orby proteins that are downstream of Ikaros or Aiolos, and wheredegradation of such protein in a patient may provide beneficial therapyor relief of symptoms to a patient in need thereof. In certaininstances, the disease state or condition may be cured.

In one embodiment, a compound or its corresponding pharmaceuticallyacceptable salt, isotopic derivative, or prodrug as described herein canbe used in an effective amount to treat a host, for example a human,with a lymphoma or lymphocytic or myelocytic proliferation disorder orabnormality. For example, a compound as described herein can beadministered to a host suffering from a Hodgkin Lymphoma or aNon-Hodgkin Lymphoma. For example, the host can be suffering from aNon-Hodgkin Lymphoma such as, but not limited to: an AIDS-RelatedLymphoma; Anaplastic Large-Cell Lymphoma; Angioimmunoblastic Lymphoma;Blastic NK-Cell Lymphoma; Burkitt's Lymphoma; Burkitt-like Lymphoma(Small Non-Cleaved Cell Lymphoma); diffuse small-cleaved cell lymphoma(DSCCL); Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma;Cutaneous T-Cell Lymphoma; Diffuse Large B-Cell Lymphoma;Enteropathy-Type T-Cell Lymphoma; Follicular Lymphoma; HepatosplenicGamma-Delta T-Cell Lymphoma; Lymphoblastic Lymphoma; Mantle CellLymphoma; Marginal Zone Lymphoma; Nasal T-Cell Lymphoma; PediatricLymphoma; Peripheral T-Cell Lymphomas; Primary Central Nervous SystemLymphoma; T-Cell Leukemias; Transformed Lymphomas; Treatment-RelatedT-Cell Lymphomas; Langerhans cell histiocytosis; or Waldenstrom'sMacroglobulinemia.

In another embodiment, a compound or its corresponding pharmaceuticallyacceptable salt, isotopic derivative, or prodrug as described herein canbe used in an effective amount to treat a host, for example a human,with a Hodgkin lymphoma, such as, but not limited to: Nodular SclerosisClassical Hodgkin's Lymphoma (CHL); Mixed Cellularity CHL;Lymphocyte-depletion CHL; Lymphocyte-rich CHL; Lymphocyte PredominantHodgkin Lymphoma; or Nodular Lymphocyte Predominant HL.

In another embodiment, a compound or its corresponding pharmaceuticallyacceptable salt, isotopic derivative, or prodrug as described herein canbe used in an effective amount to treat a host, for example a human,with an immunomodulatory condition. Non-limiting examples ofimmunomodulatory conditions include: arthritis, lupus, celiac disease,Sjogren's syndrome, polymyalgia rheumatia, multiple sclerosis,ankylosing spondylitis, type 1 diabetes, alopecia areata, vasculitis,and temporal arteritis.

In certain embodiments, the condition treated with a compound of thepresent invention is a disorder related to abnormal cellularproliferation. Abnormal cellular proliferation, notablyhyperproliferation, can occur as a result of a wide variety of factors,including genetic mutation, infection, exposure to toxins, autoimmunedisorders, and benign or malignant tumor induction.

Abnormal proliferation of B-cells, T-cells, and/or NK cells can resultin a wide range of diseases such as cancer, proliferative disorders andinflammatory/immune diseases. A host, for example a human, afflictedwith any of these disorders can be treated with an effective amount of acompound as described herein to achieve a decrease in symptoms(palliative agent) or a decrease in the underlying disease (a diseasemodifying agent).

In one embodiment, a compound or its corresponding pharmaceuticallyacceptable salt, isotopic derivative, or prodrug as described herein canbe used in an effective amount to treat a host, for example a human,with a specific B-cell lymphoma or proliferative disorder such as, butnot limited to: multiple myeloma; Diffuse large B cell lymphoma;Follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT);Small cell lymphocytic lymphoma; diffuse poorly differentiatedlymphocytic lymphoma; Mediastinal large B cell lymphoma; Nodal marginalzone B cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL);Intravascular large B-cell lymphoma; Primary effusion lymphoma; orLymphomatoid granulomatosis; B-cell prolymphocytic leukemia; Hairy cellleukemia; Splenic lymphoma/leukemia, unclassifiable; Splenic diffuse redpulp small B-cell lymphoma; Hairy cell leukemia-variant;Lymphoplasmacytic lymphoma; Heavy chain diseases, for example, Alphaheavy chain disease, Gamma heavy chain disease, Mu heavy chain disease;Plasma cell myeloma; Solitary plasmacytoma of bone; Extraosseousplasmacytoma; Primary cutaneous follicle center lymphoma; Tcell/histiocyte rich large B-cell lymphoma; DLBCL associated withchronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly;Primary mediastinal (thymic) large B-cell lymphoma; Primary cutaneousDLBCL, leg type; ALK+large B-cell lymphoma; Plasmablastic lymphoma;Large B-cell lymphoma arising in HHV8-associated multicentric; Castlemandisease; B-cell lymphoma, unclassifiable, with features intermediatebetween diffuse large B-cell lymphoma; or B-cell lymphoma,unclassifiable, with features intermediate between diffuse large B-celllymphoma and classical Hodgkin lymphoma.

In one embodiment, a compound or its corresponding pharmaceuticallysalt, isotopic derivative, or prodrug as described herein can be used inan effective amount to treat a host, for example a human, with a T-cellor NK-cell lymphoma such as, but not limited to: anaplastic lymphomakinase (ALK) positive, ALK negative anaplastic large cell lymphoma, orprimary cutaneous anaplastic large cell lymphoma; angioimmunoblasticlymphoma; cutaneous T-cell lymphoma, for example mycosis fungoides,Szary syndrome, primary cutaneous anaplastic large cell lymphoma,primary cutaneous CD30+ T-cell lymphoproliferative disorder; primarycutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma;primary cutaneous gamma-delta T-cell lymphoma; primary cutaneoussmall/medium CD4+ T-cell lymphoma, and lymphomatoid papulosis; AdultT-cell Leukemia/Lymphoma (ATLL); Blastic NK-cell Lymphoma;Enteropathy-type T-cell lymphoma; Hematosplenic gamma-delta T-cellLymphoma; Lymphoblastic Lymphoma; Nasal NK/T-cell Lymphomas;Treatment-related T-cell lymphomas; for example lymphomas that appearafter solid organ or bone marrow transplantation; T-cell prolymphocyticleukemia; T-cell large granular lymphocytic leukemia; Chroniclymphoproliferative disorder of NK-cells; Aggressive NK cell leukemia;Systemic EBV+ T-cell lymphoproliferative disease of childhood(associated with chronic active EBV infection); Hydroa vacciniforme-likelymphoma; Adult T-cell leukemia/lymphoma; Enteropathy-associated T-celllymphoma; Hepatosplenic T-cell lymphoma; or Subcutaneouspanniculitis-like T-cell lymphoma.

In one embodiment, a compound or its corresponding pharmaceuticallyacceptable salt, isotopic derivative, or prodrug as described herein canbe used to treat a host, for example a human, with leukemia. Forexample, the host may be suffering from an acute or chronic leukemia ofa lymphocytic or myelogenous origin, such as, but not limited to: Acutelymphoblastic leukemia (ALL); Acute myelogenous leukemia (AML); Chroniclymphocytic leukemia (CLL); Chronic myelogenous leukemia (CML); juvenilemyelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acutepromyelocytic leukemia (a subtype of AML); large granular lymphocyticleukemia; or Adult T-cell chronic leukemia. In one embodiment, thepatient suffers from an acute myelogenous leukemia, for example anundifferentiated AML (MO); myeloblastic leukemia (M1; with/withoutminimal cell maturation); myeloblastic leukemia (M2; with cellmaturation); promyelocytic leukemia (M3 or M3 variant [M3V]);myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]);monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblasticleukemia (M7).

There are a number of skin disorders associated with cellularhyperproliferation. Psoriasis, for example, is a benign disease of humanskin generally characterized by plaques covered by thickened scales. Thedisease is caused by increased proliferation of epidermal cells ofunknown cause. Chronic eczema is also associated with significanthyperproliferation of the epidermis. Other diseases caused byhyperproliferation of skin cells include atopic dermatitis, lichenplanus, warts, pemphigus vulgaris, actinic keratosis, basal cellcarcinoma and squamous cell carcinoma.

Other hyperproliferative cell disorders include blood vesselproliferation disorders, fibrotic disorders, autoimmune disorders,graft-versus-host rejection, tumors and cancers.

Blood vessel proliferative disorders include angiogenic and vasculogenicdisorders. Proliferation of smooth muscle cells in the course ofdevelopment of plaques in vascular tissue cause, for example,restenosis, retinopathies and atherosclerosis. Both cell migration andcell proliferation play a role in the formation of atheroscleroticlesions.

Fibrotic disorders are often due to the abnormal formation of anextracellular matrix. Examples of fibrotic disorders include hepaticcirrhosis and mesangial proliferative cell disorders. Hepatic cirrhosisis characterized by the increase in extracellular matrix constituentsresulting in the formation of a hepatic scar. Hepatic cirrhosis cancause diseases such as cirrhosis of the liver. An increasedextracellular matrix resulting in a hepatic scar can also be caused byviral infection such as hepatitis. Lipocytes appear to play a major rolein hepatic cirrhosis.

Mesangial disorders are brought about by abnormal proliferation ofmesangial cells. Mesangial hyperproliferative cell disorders includevarious human renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic micro-angiopathysyndromes, transplant rejection, and glomerulopathies.

Another disease with a proliferative component is rheumatoid arthritis.Rheumatoid arthritis is generally considered an autoimmune disease thatis thought to be associated with activity of autoreactive T cells, andto be caused by autoantibodies produced against collagen and IgE.

Other disorders that can include an abnormal cellular proliferativecomponent include Bechet's syndrome, acute respiratory distress syndrome(ARDS), ischemic heart disease, post-dialysis syndrome, leukemia,acquired immune deficiency syndrome, vasculitis, lipid histiocytosis,septic shock and inflammation in general.

A compound or its pharmaceutically acceptable salt, isotopic analog, orprodrug as described herein can be used in an effective amount to treata host, for example a human, with a proliferative condition such asmyeloproliferative disorder (MPD), polycythemia vera (PV), essentialthrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM),chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome(HES), system mast cell disease (SMCD), and the like. In anotherembodiment, a compound provided herein is useful for the treatment ofprimary myelofibrosis, post-polycythemia vera myelofibrosis,post-essential thrombocythemia myelofibrosis, and secondary acutemyelogenous leukemia.

In one embodiment, a compound or its pharmaceutically acceptable salt,isotopic analog, or prodrug as described herein can be used in aneffective amount to treat a host, for example a human, with amyelodysplastic syndrome (MDS) such as, but not limited to: refractorycytopenia with unilineage dysplasia, refractory anemia with ringsideroblasts (RARS), refractory anemia with ringsideroblasts-thrombocytosis (RARS-t), refractory cytopenia withmultilineage dyslplasia (RCMD) including RCMD with multilineagedysplasia and ring sideroblasts (RCMD-RS), Refractory amenias withexcess blasts I (RAEB-I) and II (RAEB-II), 5q-syndrome, refractorycytopenia of childhood, and the like.

In one embodiment a compound of the present invention can provide atherapeutic effect by direct degradation of Ikaros or Aiolos which maychange the transcriptional regulation of a protein downstream of Ikarosor Aiolos.

The term “neoplasia” or “cancer” is used to refer to the pathologicalprocess that results in the formation and growth of a cancerous ormalignant neoplasm, i.e., abnormal tissue that grows by cellularproliferation, often more rapidly than normal and continues to growafter the stimuli that initiated the new growth cease. Malignantneoplasms show partial or complete lack of structural organization andfunctional coordination with the normal tissue and most invadesurrounding tissues, metastasize to several sites, and are likely torecur after attempted removal and to cause the death of the patientunless adequately treated. As used herein, the term neoplasia is used todescribe all cancerous disease states and embraces or encompasses thepathological process associated with malignant hematogenous, ascitic andsolid tumors. Exemplary cancers which may be treated by the presentcompounds either alone or in combination with at least one additionalanti-cancer agent include squamous-cell carcinoma, basal cell carcinoma,adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas,cancer of the bladder, bowel, breast, cervix, colon, esophagus, head,kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach;leukemias; benign and malignant lymphomas, particularly Burkitt'slymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; sarcomas, including Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using compounds according to the present invention include, forexample, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineagelymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cellLeukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, BurkittsLymphoma, B-cell ALL, Philadelphia chromosome positive ALL andPhiladelphia chromosome positive CML.

Additional cancers which may be treated using the disclosed compoundsaccording to the present invention include, for example, acutegranulocytic leukemia, acute lymphocytic leukemia (ALL), acutemyelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenalcancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma,angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Celllymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrowcancer, bowel cancer, brain cancer, brain stem glioma, breast cancer,triple (estrogen, progesterone and HER-2) negative breast cancer, doublenegative breast cancer (two of estrogen, progesterone and HER-2 arenegative), single negative (one of estrogen, progesterone and HER-2 isnegative), estrogen-receptor positive, HER2-negative breast cancer,estrogen receptor-negative breast cancer, estrogen receptor positivebreast cancer, metastatic breast cancer, luminal A breast cancer,luminal B breast cancer, Her2-negative breast cancer, HER2-positive ornegative breast cancer, progesterone receptor-negative breast cancer,progesterone receptor-positive breast cancer, recurrent breast cancer,carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma,chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma,cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ(DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophagealcancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer,fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer,gastrointestinal cancer, gastrointestinal carcinoid cancer,gastrointestinal stromal tumors (GIST), germ cell tumor glioblastomamultiforme (GBM), glioma, hairy cell leukemia, head and neck cancer,hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer,infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma(ILC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepaticbile duct cancer, invasive/infiltrating breast cancer, Islet cellcancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer,leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer,liposarcoma, liver cancer, lobular carcinoma in situ, low-gradeastrocytoma, lung cancer, lymph node cancer, lymphoma, male breastcancer, medullary carcinoma, medulloblastoma, melanoma, meningioma,Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous,mesothelioma metastatic breast cancer, metastatic melanoma metastaticsquamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancermucinous carcinoma, mucosal melanoma, multiple myeloma, MycosisFungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngealcancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs),non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cellcancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer,oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma,osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germcell tumor, ovarian primary peritoneal carcinoma, ovarian sex cordstromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma,paranasal sinus cancer, parathyroid cancer, pelvic cancer, penilecancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,pheochromocytoma, pilocytic astrocytoma, pineal region tumor,pineoblastoma, pituitary gland cancer, primary central nervous system(CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma,renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, softtissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, smallcell lung cancer (SCLC), small intestine cancer, spinal cancer, spinalcolumn cancer, spinal cord cancer, squamous cell carcinoma, stomachcancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throatcancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsilcancer, transitional cell cancer, tubal cancer, tubular carcinoma,undiagnosed cancer, ureteral cancer, urethral cancer, uterineadenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvarcancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-celllineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, AdultT-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma,Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL,Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia(JMML), acute promyelocytic leukemia (a subtype of AML), large granularlymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large Bcell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissuelymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large Bcell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenicmarginal zone lymphoma (SMZL); intravascular large B-cell lymphoma;primary effusion lymphoma; or lymphomatoid granulomatosis; B-cellprolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable,splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacyticlymphoma; heavy chain diseases, for example, Alpha heavy chain disease,Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma,solitary plasmacytoma of bone; extraosseous plasmacytoma; primarycutaneous follicle center lymphoma, T cell/histocyte rich large B-celllymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus(EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-celllymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma,plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associatedmulticentric, Castleman disease; B-cell lymphoma, unclassifiable, withfeatures intermediate between diffuse large B-cell lymphoma, or B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and classical Hodgkin lymphoma. In one embodimentthe disorder is adenoid cystic carcinoma. In one embodiment the disorderis NUT midline carcinoma.

In another embodiment, a compound or its pharmaceutically acceptablesalt, isotopic derivative or prodrug as described herein can be used inan effective amount to treat a host, for example a human, with anautoimmune disorder. Examples include, but are not limited to: Acutedisseminated encephalomyelitis (ADEM); Addison's disease;Agammaglobulinemia; Alopecia areata; Amyotrophic lateral sclerosis (AlsoLou Gehrig's disease; Motor Neuron Disease); Ankylosing Spondylitis;Antiphospholipid syndrome; Antisynthetase syndrome; Atopic allergy;Atopic dermatitis; Autoimmune aplastic anemia; Autoimmune arthritis;Autoimmune cardiomyopathy; Autoimmune enteropathy; Autoimmunegranulocytopenia; Autoimmune hemolytic anemia; Autoimmune hepatitis;Autoimmune hypoparathyroidism; Autoimmune inner ear disease; Autoimmunelymphoproliferative syndrome; Autoimmune myocarditis; Autoimmunepancreatitis; Autoimmune peripheral neuropathy; Autoimmune ovarianfailure; Autoimmune polyendocrine syndrome; Autoimmune progesteronedermatitis; Autoimmune thrombocytopenic purpura; Autoimmune thyroiddisorders; Autoimmune urticarial; Autoimmune uveitis; Autoimmunevasculitis; Balo disease/Balo concentric sclerosis; Behcet's disease;Berger's disease; Bickerstaff s encephalitis; Blau syndrome; Bullouspemphigoid; Cancer; Castleman's disease; Celiac disease; Chagas disease;Chronic inflammatory demyelinating polyneuropathy; Chronic inflammatorydemyelinating polyneuropathy; Chronic obstructive pulmonary disease;Chronic recurrent multifocal osteomyelitis; Churg-Strauss syndrome;Cicatricial pemphigoid; Cogan syndrome; Cold agglutinin disease;Complement component 2 deficiency; Contact dermatitis; Cranialarteritis; CREST syndrome; Crohn's disease; Cushing's Syndrome;Cutaneous leukocytoclastic angiitis; Dego's disease; Dercum's disease;Dermatitis herpetiformis; Dermatomyositis; Diabetes mellitus type 1;Diffuse cutaneous systemic sclerosis; Discoid lupus erythematosus;Dressler's syndrome; Drug-induced lupus; Eczema; Endometriosis;Enthesitis-related arthritis; Eosinophilic fasciitis; Eosinophilicgastroenteritis; Eosinophilic pneumonia; Epidermolysis bullosaacquisita; Erythema nodosum; Erythroblastosis fetalis; Essential mixedcryoglobulinemia; Evan's syndrome; Extrinsic and intrinsic reactiveairways disease (asthma); Fibrodysplasia ossificans progressive;Fibrosing alveolitis (or Idiopathic pulmonary fibrosis); Gastritis;Gastrointestinal pemphigoid; Glomerulonephritis; Goodpasture's syndrome;Graves' disease; Guillain-Barre syndrome (GBS); Hashimoto'sencephalopathy; Hashimoto's thyroiditis; Hemolytic anemia;Henoch-Schonlein purpura; Herpes gestationis (Gestational Pemphigoid);Hidradenitis suppurativa; Hughes-Stovin syndrome; Hypogammaglobulinemia;Idiopathic inflammatory demyelinating diseases; Idiopathic pulmonaryfibrosis; Idiopathic thrombocytopenic purpura; IgA nephropathy; Immuneglomerulonephritis; Immune nephritis; Immune pneumonitis; Inclusion bodymyositis; inflammatory bowel disease; Interstitial cystitis; Juvenileidiopathic arthritis aka Juvenile rheumatoid arthritis; Kawasaki'sdisease; Lambert-Eaton myasthenic syndrome; Leukocytoclastic vasculitis;Lichen planus; Lichen sclerosus; Linear IgA disease (LAD); Lupoidhepatitis aka Autoimmune hepatitis; Lupus erythematosus; Majeedsyndrome; microscopic polyangiitis; Miller-Fisher syndrome; mixedconnective tissue disease; Morphea; Mucha-Habermann disease akaPityriasis lichenoides et varioliformis acuta; Multiple sclerosis;Myasthenia gravis; Myositis; Méniére's disease; Narcolepsy;Neuromyelitis optica (also Devic's disease); Neuromyotonia; Occularcicatricial pemphigoid; Opsoclonus myoclonus syndrome; Ord'sthyroiditis; Palindromic rheumatism; PANDAS (pediatric autoimmuneneuropsychiatric disorders associated with streptococcus);Paraneoplastic cerebellar degeneration; Paroxysmal nocturnalhemoglobinuria (PNH); Parry Romberg syndrome; Pars planitis;Parsonage-Turner syndrome; Pemphigus vulgaris; Perivenousencephalomyelitis; Pernicious anaemia; POEMS syndrome; Polyarteritisnodosa; Polymyalgia rheumatic; Polymyositis; Primary biliary cirrhosis;Primary sclerosing cholangitis; Progressive inflammatory neuropathy;Psoriasis; Psoriatic arthritis; pure red cell aplasia; Pyodermagangrenosum; Rasmussen's encephalitis; Raynaud phenomenon; Reiter'ssyndrome; relapsing polychondritis; restless leg syndrome;retroperitoneal fibrosis; rheumatic fever; rheumatoid arthritis;Sarcoidosis; Schizophrenia; Schmidt syndrome; Schnitzler syndrome;Scleritis; Scleroderma; Sclerosing cholangitis; serum sickness;Sjögren's syndrome; Spondyloarthropathy; Stiff person syndrome; Still'sdisease; Subacute bacterial endocarditis (SBE); Susac's syndrome;Sweet's syndrome; Sydenham chorea; sympathetic ophthalmia; systemiclupus erythematosus; Takayasu's arteritis; temporal arteritis (alsoknown as “giant cell arteritis”); thrombocytopenia; Tolosa-Huntsyndrome; transverse myelitis; ulcerative colitis; undifferentiatedconnective tissue disease; undifferentiated spondyloarthropathy;urticarial vasculitis; vasculitis; vitiligo; viral diseases such asEpstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1,Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV); orWegener's granulomatosis. In some embodiments, the autoimmune disease isan allergic condition, including those from asthma, food allergies,atopic dermatitis, chronic pain, and rhinitis.

Cutaneous contact hypersensitivity and asthma are just two examples ofimmune responses that can be associated with significant morbidity.Others include atopic dermatitis, eczema, Sjogren's Syndrome, includingkeratoconjunctivitis sicca secondary to Sjogren's Syndrome, alopeciaareata, allergic responses due to arthropod bite reactions, Crohn'sdisease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis,ulcerative colitis, cutaneous lupus erythematosus, scleroderma,vaginitis, proctitis, and drug eruptions. These conditions may result inany one or more of the following symptoms or signs: itching, swelling,redness, blisters, crusting, ulceration, pain, scaling, cracking, hairloss, scarring, or oozing of fluid involving the skin, eye, or mucosalmembranes.

In atopic dermatitis, and eczema in general, immunologically mediatedleukocyte infiltration (particularly infiltration of mononuclear cells,lymphocytes, neutrophils, and eosinophils) into the skin importantlycontributes to the pathogenesis of these diseases. Chronic eczema alsois associated with significant hyperproliferation of the epidermis.Immunologically mediated leukocyte infiltration also occurs at sitesother than the skin, such as in the airways in asthma and in the tearproducing gland of the eye in keratoconjunctivitis sicca.

A compound or its pharmaceutically acceptable salt, isotopic variant, orprodrug as described herein can be used in an effective amount to treata host, for example a human, with a skin disorder such as psoriasis (forexample, psoriasis vulgaris), atopic dermatitis, skin rash, skinirritation, skin sensitization (e.g., contact dermatitis or allergiccontact dermatitis). For example, certain substances including somepharmaceuticals when topically applied can cause skin sensitization. Insome embodiments, the skin disorder is treated by topical administrationof compounds known in the art in combination with the compoundsdisclosed herein. In one non-limiting embodiment compounds of thepresent invention are used as topical agents in treating contactdermatitis, atopic dermatitis, eczematous dermatitis, psoriasis,Sjogren's Syndrome, including keratoconjunctivitis sicca secondary toSjogren's Syndrome, alopecia areata, allergic responses due to arthropodbite reactions, Crohn's disease, aphthous ulcer, iritis, conjunctivitis,keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma,cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, anddrug eruptions. The novel method may also be useful in reducing theinfiltration of skin by malignant leukocytes in diseases such as mycosisfungoides.

Disease states of conditions which may be treated using compoundsaccording to the present invention include, for example, asthma,autoimmune diseases such as multiple sclerosis, various cancers,ciliopathies, cleft palate, diabetes, heart disease, hypertension,inflammatory bowel disease, mental retardation, mood disorder, obesity,refractive error, infertility, Angelman syndrome, Canavan disease,Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchennemuscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter'ssyndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease1 (PKD1) or 2 (PKD2) Prader-Willi syndrome, Sickle-cell disease,Tay-Sachs disease, Turner syndrome.

Further disease states or conditions which may be treated by compoundsaccording to the present invention include Alzheimer's disease,Amyotrophic lateral sclerosis (Lou Gehrig's disease), Anorexia nervosa,Anxiety disorder, Atherosclerosis, Attention deficit hyperactivitydisorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronicobstructive pulmonary disease, Crohn's disease, Coronary heart disease,Dementia, Depression, Diabetes mellitus type 1, Diabetes mellitus type2, Epilepsy, Guillain-Barr syndrome, Irritable bowel syndrome, Lupus,Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity,Obsessive-compulsive disorder, Panic disorder, Parkinson's disease,Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke,Thromboangiitis obliterans, Tourette syndrome, Vasculitis.

Still additional disease states or conditions which can be treated bycompounds according to the present invention include aceruloplasminemia,Achondrogenesis type II, achondroplasia, Acrocephaly, Gaucher diseasetype 2, acute intermittent porphyria, Canavan disease, AdenomatousPolyposis Coli, ALA dehydratase deficiency, adenylosuccinate lyasedeficiency, Adrenogenital syndrome, Adrenoleukodystrophy, ALA-Dporphyria, ALA dehydratase deficiency, Alkaptonuria, Alexander disease,Alkaptonuric ochronosis, alpha 1-antitrypsin deficiency, alpha-1proteinase inhibitor, emphysema, amyotrophic lateral sclerosis Alströmsyndrome, Alexander disease, Amelogenesis imperfecta, ALA dehydratasedeficiency, Anderson-Fabry disease, androgen insensitivity syndrome,Anemia Angiokeratoma Corporis Diffusum, Angiomatosis retinae (vonHippel-Lindau disease) Apert syndrome, Arachnodactyly (Marfan syndrome),Stickler syndrome, Arthrochalasis multiplex congenital (Ehlers-Danlossyndrome #arthrochalasia type) ataxia telangiectasia, Rett syndrome,primary pulmonary hypertension, Sandhoff disease, neurofibromatosis typeII, Beare-Stevenson cutis gyrata syndrome, Mediterranean fever,familial, Benjamin syndrome, beta-thalassemia, Bilateral AcousticNeurofibromatosis (neurofibromatosis type II), factor V Leidenthrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloomsyndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome(Turner syndrome), Bourneville disease (tuberous sclerosis), priondisease, Birt-Hogg-Dubé syndrome, Brittle bone disease (osteogenesisimperfecta), Broad Thumb-Hallux syndrome (Rubinstein-Taybi syndrome),Bronze Diabetes/Bronzed Cirrhosis (hemochromatosis), Bulbospinalmuscular atrophy (Kennedy's disease), Burger-Grutz syndrome (lipoproteinlipase deficiency), CGD Chronic granulomatous disorder, Campomelicdysplasia, biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cridu chat, CAVD (congenital absence of the vas deferens), Caylorcardiofacial syndrome (CBAVD), CEP (congenital erythropoieticporphyria), cystic fibrosis, congenital hypothyroidism, Chondrodystrophysyndrome (achondroplasia), otospondylomegaepiphyseal dysplasia,Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome,Thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome,(familial adenomatous polyposis), Congenital erythropoietic porphyria,Congenital heart disease, Methemoglobinemia/Congenitalmethaemoglobinaemia, achondroplasia, X-linked sideroblastic anemia,Connective tissue disease, Conotruncal anomaly face syndrome, Cooley'sAnemia (beta-thalassemia), Copper storage disease (Wilson's disease),Copper transport disease (Menkes disease), hereditary coproporphyria,Cowden syndrome, Craniofacial dysarthrosis (Crouzon syndrome),Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowdensyndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy),Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria,spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophy,Duchenne and Becker types (DBMD), Usher syndrome, Degenerative nervediseases including de Grouchy syndrome and Dejerine-Sottas syndrome,developmental disabilities, distal spinal muscular atrophy, type V,androgen insensitivity syndrome, Diffuse Globoid Body Sclerosis (Krabbedisease), Di George's syndrome, Dihydrotestosterone receptor deficiency,androgen insensitivity syndrome, Down syndrome, Dwarfism, erythropoieticprotoporphyria Erythroid 5-aminolevulinate synthetase deficiency,Erythropoietic porphyria, erythropoietic protoporphyria, erythropoieticuroporphyria, Friedreich's ataxia-familial paroxysmal polyserositis,porphyria cutanea tarda, familial pressure sensitive neuropathy, primarypulmonary hypertension (PPH), Fibrocystic disease of the pancreas,fragile X syndrome, galactosemia, genetic brain disorders, Giant cellhepatitis (Neonatal hemochromatosis), Gronblad-Strandberg syndrome(pseudoxanthoma elasticum), Gunther disease (congenital erythropoieticporphyria), haemochromatosis, Hallgren syndrome, sickle cell anemia,hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease(von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilfordprogeria syndrome (progeria), Hyperandrogenism, Hypochondroplasia,Hypochromic anemia, Immune system disorders, including X-linked severecombined immunodeficiency, Insley-Astley syndrome, Jackson-Weisssyndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weisssyndrome, Kidney diseases, including hyperoxaluria, Klinefelter'ssyndrome, Kniest dysplasia, Lacunar dementia, Langer-Saldinoachondrogenesis, ataxia telangiectasia, Lynch syndrome,Lysyl-hydroxylase deficiency, Machado-Joseph disease, Metabolicdisorders, including Kniest dysplasia, Marfan syndrome, Movementdisorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome,Multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeneychondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffersyndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, Polycystickidney disease, polyostotic fibrous dysplasia (McCune-Albrightsyndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome,hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome),primary pulmonary hypertension, primary senile degenerative dementia,prion disease, progeria (Hutchinson Gilford Progeria Syndrome),progressive chorea, chronic hereditary (Huntington) (Huntington'sdisease), progressive muscular atrophy, spinal muscular atrophy,propionic acidemia, protoporphyria, proximal myotonic dystrophy,pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb(retinoblastoma), Recklinghausen disease (neurofibromatosis type I),Recurrent polyserositis, Retinal disorders, Retinoblastoma, Rettsyndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levysyndrome, severe achondroplasia with developmental delay and acanthosisnigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia, andadrenal gland (SBLA) syndrome, sclerosis tuberose (tuberous sclerosis),SDAT, SED congenital (spondyloepiphyseal dysplasia congenita), SEDStrudwick (spondyloepimetaphyseal dysplasia, Strudwick type), SEDc(spondyloepiphyseal dysplasia congenita) SEMD, Strudwick type(spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen syndrome,Skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South-Africangenetic porphyria (variegate porphyria), infantile-onset ascendinghereditary spastic paralysis, Speech and communication disorders,sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Sticklersyndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterindeficiency, beta-thalassemia, Thyroid disease, Tomaculous neuropathy(hereditary neuropathy with liability to pressure palsies), TreacherCollins syndrome, Triplo X syndrome (triple X syndrome), Trisomy 21(Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease),Vision impairment and blindness (Alström syndrome), Vrolik disease,Waardenburg syndrome, Warburg Sjo Fledelius Syndrome, Wolf-Hirschhornsyndrome, Wolff Periodic disease, Weissenbacher-Zweymüller syndrome andXeroderma pigmentosum, among others.

In one embodiment, a method is provided for treating multiple myelomacomprising administering to a patient an effective amount of a compoundof Formula I or Formula II, or a pharmaceutically acceptable salt,isotopic analog, or prodrug thereof, optionally in a pharmaceuticallyacceptable carrier to form a composition. In another embodiment, acompound of Formula I or Formula II, or a pharmaceutically acceptablesalt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition, for use in amethod of treating multiple myeloma, wherein the method comprisesadministering the compound to a patient.

In one embodiment, a method is provided for managing the progression ofmultiple myeloma comprising administering to a patient an effectiveamount of a compound of Formula I or Formula II, or a pharmaceuticallyacceptable salt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition. In anotherembodiment, a compound of Formula I or Formula II, or a pharmaceuticallyacceptable salt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition, for use in amethod of managing the progression of multiple myeloma, wherein themethod comprises administering the compound to a patient.

In one embodiment, a method is provided for inducing a therapeuticresponse as assessed by the International Uniform Response Criteria(IURC) for Multiple Myeloma (described in Durie B. G. M; et al.“International uniform response criteria for multiple myeloma. Leukemia2006, 10(10):1-7) in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound ofFormula I or Formula II, or a pharmaceutically acceptable salt, isotopicanalog, or prodrug thereof, optionally in a pharmaceutically acceptablecarrier to form a composition.

In another embodiment, a method is provided to achieve a stringentcomplete response, complete response, or very good partial response, asassessed by the IURC for Multiple Myeloma in a patient having multiplemyeloma comprising administering to the patient an effective amount of acompound of Formula I or Formula II, or a pharmaceutically acceptablesalt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition.

In another embodiment, a method is provided to achieve an increase inoverall survival, progression-free survival, event-free survival, timeto process, or disease-free survival in a patient having multiplemyeloma comprising administering to the patient an effective amount of acompound of Formula I or Formula II, or a pharmaceutically acceptablesalt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition.

In another embodiment, a method is provided to achieve an increase inoverall survival in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound ofFormula I or Formula II, or a pharmaceutically acceptable salt, isotopicanalog, or prodrug thereof, optionally in a pharmaceutically acceptablecarrier to form a composition.

In another embodiment, a method is provided to achieve an increase inprogression-free survival in a patient having multiple myelomacomprising administering to the patient an effective amount of acompound of Formula I or Formula II, or a pharmaceutically acceptablesalt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition.

In another embodiment, a method is provided to achieve an increase inevent-free survival in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound ofFormula I or Formula II, or a pharmaceutically acceptable salt, isotopicanalog, or prodrug thereof, optionally in a pharmaceutically acceptablecarrier to form a composition.

In another embodiment, a method is provided to achieve an increase intime to progression in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound ofFormula I or Formula II, or a pharmaceutically acceptable salt, isotopicanalog, or prodrug thereof, optionally in a pharmaceutically acceptablecarrier to form a composition.

In another embodiment, a method is provided to achieve an increase indisease-free survival in a patient having multiple myeloma comprisingadministering to the patient an effective amount of a compound ofFormula I or Formula II, or a pharmaceutically acceptable salt, isotopicanalog, or prodrug thereof, optionally in a pharmaceutically acceptablecarrier to form a composition.

Methods are also provided to treat patients who have been previouslytreated for multiple myeloma but are non-responsive to standardtherapies in addition to those who have not been previously treated.Additional methods are provided to treat patients who have undergonesurgery in an attempt to treat multiple myeloma in addition to those whohave not undergone surgery. Methods are also provided to treat patientswho have previously undergone transplant therapy in addition to thosewho have not.

The compounds described herein may be used in the treatment ormanagement of multiple myeloma that is relapsed, refractory, orresistant. In some embodiments, the multiple myeloma is primary,secondary, tertiary, quadruply or quintuply relapsed. In one embodiment,the compounds described herein may be used to reduce, maintain, oreliminate minimal residual disease (MRD).

The types of multiple myeloma that may be treated with the compoundsdescribed herein include, but are not limited to: monoclonal gammopathyof undetermined significance (MGUS); low risk, intermediate risk, orhigh risk multiple myeloma; newly diagnosed multiple myeloma, includinglow risk, intermediate risk, or high risk newly diagnosed multiplemyeloma); transplant eligible and transplant ineligible multiplemyeloma; smoldering (indolent) multiple myeloma (including low risk,intermediate risk, or high risk smoldering multiple myeloma); activemultiple myeloma; solitary plasmocytoma; plasma cell leukemia; centralnervous system multiple myeloma; light chain myeloma; non-secretorymyeloma; Immunoglobulin D myeloma; and Immunoglobulin E myeloma.

In some embodiments, the compounds described herein may be used in thetreatment or management of multiple myeloma characterized by geneticabnormalities, for example but not limited to: Cyclin D translocations(for example, t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32); ort(6;20);); MMSET translocations (for example t(4;14)(p16;q32); MAFtranslocations (for example t(14;16)(q32;a32); t(20;22);t(16;22)(q11;q13); or t(14;20)(q32;q11); or other chromosome factors(for example deletion of 17p13 or chromosome 13; del(17/17p),nonhyperdiploidy, and gain (1q)).

In one embodiment, a method is provided for treating or managingmultiple myeloma comprising administering to a patient an effectiveamount of a compound of Formula I or Formula II, or a pharmaceuticallyacceptable salt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition, as inductiontherapy.

In one embodiment, a method is provided for treating or managingmultiple myeloma comprising administering to a patient an effectiveamount of a compound of Formula I or Formula II, or a pharmaceuticallyacceptable salt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition, asconsolidation therapy.

In one embodiment, a method is provided for treating or managingmultiple myeloma comprising administering to a patient an effectiveamount of a compound of Formula I or Formula II, or a pharmaceuticallyacceptable salt, isotopic analog, or prodrug thereof, optionally in apharmaceutically acceptable carrier to form a composition, asmaintenance therapy.

In one embodiment, the multiple myeloma is plasma cell leukemia.

In one embodiment, the multiple myeloma is high risk multiple myeloma.In some embodiments, the high risk multiple myeloma is relapsed orrefractory. In one embodiment, the high risk multiple myeloma hasrelapsed within 12 months of the first treatment. In another embodiment,the high risk multiple myeloma is characterized by geneticabnormalities, for example, one or more of del(17/17p) andt(14;16)(q32;q32). In some embodiments, the high risk multiple myelomais relapsed or refractory to one, two or three previous treatments.

In one embodiment, the multiple myeloma has a p53 mutation. In oneembodiment, the p53 mutation is a Q331 mutation. In one embodiment, thep53 mutation is a R273H mutation. In one embodiment, the p53 mutation isa K132 mutation. In one embodiment, the p53 mutation is a K132Nmutation. In one embodiment, the p53 mutation is a R337 mutation. In oneembodiment, the p53 mutation is a R337L mutation. In one embodiment, thep53 mutation is a W146 mutation. In one embodiment, the p53 mutation isa S261 mutation. In one embodiment, the p53 mutation is a S261Tmutation. In one embodiment, the p53 mutation is a E286 mutation. In oneembodiment, the p53 mutation is a E286K mutation. In one embodiment, thep53 mutation is a R175 mutation. In one embodiment, the p53 mutation isa R175H mutation. In one embodiment, the p53 mutation is a E258mutation. In one embodiment, the p53 mutation is a E258K mutation. Inone embodiment, the p53 mutation is a A161 mutation. In one embodiment,the p53 mutation is a A161T mutation.

In one embodiment, the multiple myeloma has a homozygous deletion ofp53. In one embodiment, the multiple myeloma has a homozygous deletionof wild-type p53. In one embodiment, the multiple myeloma has wild-typep53.

In one embodiment, the multiple myeloma shows activation of one or moreoncogenic drivers. In one embodiment, the one or more oncogenic driversare selected from the group consisting of C-MAF, MAFB, FGFR3, MMset,Cyclin D1, and Cyclin D. In one embodiment, the multiple myeloma showsactivation of C-MAF. In one embodiment, the multiple myeloma showsactivation of MAFB. In one embodiment, the multiple myeloma showsactivation of FGFR3 and MMset. In one embodiment, the multiple myelomashows activation of C-MAF, FGFR3, and MMset. In one embodiment, themultiple myeloma shows activation of Cyclin D1. In one embodiment, themultiple myeloma shows activation of MAFB and Cyclin D1. In oneembodiment, the multiple myeloma shows activation of Cyclin D.

In one embodiment, the multiple myeloma has one or more chromosomaltranslocations. In one embodiment, the chromosomal translocation ist(14;16). In one embodiment, the chromosomal translocation is t(14;20).In one embodiment, the chromosomal translocation is t(4; 14). In oneembodiment, the chromosomal translocations are t(4;14) and t(14;16). Inone embodiment, the chromosomal translocation is t(11;14). In oneembodiment, the chromosomal translocation is t(6;20). In one embodiment,the chromosomal translocation is t(20;22). In one embodiment, thechromosomal translocations are t(6;20) and t(20;22). In one embodiment,the chromosomal translocation is t(16;22). In one embodiment, thechromosomal translocations are t(14;16) and t(16;22). In one embodiment,the chromosomal translocations are t(14;20) and t(11;14).

In one embodiment, the multiple myeloma has a Q331 p53 mutation,activation of C-MAF, and a chromosomal translocation at t(14; 16). Inone embodiment, the multiple myeloma has homozygous deletion of p53,activation of C-MAF, and a chromosomal translocation at t(14; 16). Inone embodiment, the multiple myeloma has a K132N p53 mutation,activation of MAFB, and a chromosomal translocation at t(14;20). In oneembodiment, the multiple myeloma has wild type p53, activation of FGFR3and MMset, and a chromosomal translocation at t(4; 14). In oneembodiment, the multiple myeloma has wild type p53, activation of C-MAF,and a chromosomal translocation at t(14;16). In one embodiment, themultiple myeloma has homozygous deletion of p53, activation of FGFR3,MMset, and C-MAF, and chromosomal translocations at t(4;14) andt(14;16). In one embodiment, the multiple myeloma has homozygousdeletion of p53, activation of Cyclin D1, and a chromosomaltranslocation at t(11;14). In one embodiment, the multiple myeloma has aR337L p53 mutation, activation of Cyclin D1, and a chromosomaltranslocation at t(11;14). In one embodiment, the multiple myeloma has aW146 p53 mutation, activation of FGFR3 and MMset, and a chromosomaltranslocation at t(4; 14). In one embodiment, the multiple myeloma has aS261T p53 mutation, activation of MAFB, and chromosomal translocationsat t(6;20) and t(20;22). In one embodiment, the multiple myeloma has aE286K p53 mutation, by activation of FGFR3 and MMset, and a chromosomaltranslocation at t(4; 14). In one embodiment, the multiple myeloma has aR175H p53 mutation, activation of FGFR3 and MMset, and a chromosomaltranslocation at t(4; 14). In one embodiment, the multiple myeloma has aE258K p53 mutation, activation of C-MAF, and chromosomal translocationsat t(14;16) and t(16;22). In one embodiment, the multiple myeloma haswild type p53, activation of MAFB and Cyclin D1, and chromosomaltranslocations at t(14;20) and t(11;14). In one embodiment, the multiplemyeloma has a A161T p53 mutation, activation of Cyclin D, and achromosomal translocation at t(11;14).

In some embodiments, the multiple myeloma is transplant eligible newlydiagnosed multiple myeloma. In other embodiments, the multiple myelomais transplant ineligible newly diagnosed multiple myeloma.

In some embodiments, the multiple myeloma shows early progression (forexample less than 12 months) following initial treatment. In otherembodiments, the multiple myeloma shows early progression (for exampleless than 12 months) following autologous stem cell transplant. Inanother embodiment, the multiple myeloma is refractory to lenalidomide.In another embodiment, the multiple myeloma is refractory topomalidomide. In some such embodiments, the multiple myeloma ispredicted to be refractory to pomalidomide (for example, by molecularcharacterization). In another embodiment, the multiple myeloma isrelapsed or refractory to 3 or more treatments and was exposed to aproteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib,oprozomib, or marizomib) and an immunomodulatory compound (for examplethalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide), ordouble refractory to a proteasome inhibitor and an immunomodulatorycompound. In still other embodiments, the multiple myeloma is relapsedor refractory to 3 or more prior therapies, including for example, aCD38 monoclonal antibody (CD38 mAb, for example, daratumumab orisatuximab), a proteasome inhibitor (for example, bortezomib,carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound(for example thalidomide, lenalidomide, pomalidomide, iberdomide, oravadomide) or double refractory to a proteasome inhibitor orimmunomodulatory compound and a CD38 mAb. In still other embodiments,the multiple myeloma is triple refractory, for example, the multiplemyeloma is refractory to a proteasome inhibitor (for example,bortezomib, carfilzomib, ixazomib, oprozomib or marizomib), animmunomodulatory compound (for example thalidomide, lenalidomide,pomalidomide, iberdomide, or avadomide), and one other active agent, asdescribed herein.

In one embodiment, a method is provided for treating or managingrelapsed or refractory multiple myeloma in patients with impaired renalfunction or a symptom thereof comprising administering to a patient aneffective amount of a compound of Formula I or Formula II, or apharmaceutically acceptable salt, isotopic analog, or prodrug thereof,optionally in a pharmaceutically acceptable carrier to form acomposition.

In another embodiment, a method is provided for treating or managingrelapsed or refractory multiple myeloma in frail patients comprisingadministering to a patient an effective amount of a compound of FormulaI or Formula II, or a pharmaceutically acceptable salt, isotopic analog,or prodrug thereof, optionally in a pharmaceutically acceptable carrierto form a composition, wherein the frail patient is characterized byineligibility for induction therapy or intolerance to dexamethasonetreatment. In other embodiments, the frail patient is elderly, forexample, older than 65 years old.

In another embodiment, a method is provided for treating or managingfourth line relapsed or refractory multiple myeloma comprisingadministering to a patient an effective amount of a compound of FormulaI or Formula II, or a pharmaceutically acceptable salt, isotopic analog,or prodrug thereof, optionally in a pharmaceutically acceptable carrierto form a composition.

In another embodiment, a method is provided for treating or managingnewly diagnosed, transplant-ineligible multiple myeloma comprisingadministering to a patient an effective amount of a compound of FormulaI or Formula II, or a pharmaceutically acceptable salt, isotopic analog,or prodrug thereof, optionally in a pharmaceutically acceptable carrierto form a composition.

In another embodiment, a method is provided for treating or managingnewly diagnosed, transplant-ineligible multiple myeloma comprisingadministering to a patient an effective amount of a compound of FormulaI or Formula II, or a pharmaceutically acceptable salt, isotopic analog,or prodrug thereof, optionally in a pharmaceutically acceptable carrierto form a composition, as maintenance therapy after another therapy ortransplant.

In another embodiment, a method is provided for treating or managinghigh risk multiple myeloma that is relapsed or refractory to one, two,or three previous treatments comprising administering to a patient aneffective amount of a compound of Formula I or Formula II, or apharmaceutically acceptable salt, isotopic analog, or prodrug thereof,optionally in a pharmaceutically acceptable carrier to form acomposition.

In some embodiments, the patient to be treated by one of the compoundsdescribed herein has not be treated with multiple myeloma therapy priorto administration. In some embodiments, the patient to be treated by oneof the compounds described herein has been treated by multiple myelomatherapy prior to administration. In some embodiments, the patient to betreated by one of the compounds described herein has developed drugresistant to the multiple myeloma therapy. In some embodiments, thepatient to be treated by one of the compounds described herein hasdeveloped resistance to one, two, or three multiple myeloma therapies,wherein the therapies are selected from a CD38 antibody (CD38 mAB, forexample, daratumumab or isatuximab), a proteasome inhibitor (forexample, bortezomib, carfilzomib, ixazomib, or marizomib), and animmunomodulatory compound (for example thalidomide, lenalidomide,pomalidomide, iberdomide, or avodomide).

The compounds described herein can be used to treat a patient regardlessof patient's age. In some embodiments, the subject is 18 years or older.In other embodiments, the subject is more than 18, 25, 35, 40, 45, 50,55, 60, 65, or 70 years old. In other embodiments, the patient is lessthan 65 years old. In other embodiments, the patient is more than 65years old. In one embodiment, the patient is an elderly multiple myelomapatient, such as a patient older than 65 years old. In one embodiment,the patient is an elderly multiple myeloma patient, such as a patientolder than 75 years old.

IV. Combination Therapy

Any of the compounds described herein can be used in an effective amountalone or in combination to treat a host such as a human with a disorderas described herein.

The term “bioactive agent” or “additional therapeutically active agent”is used to describe an agent, other than the compound according to thepresent invention, which can be used in combination or alternation witha compound of the present invention to achieve a desired result oftherapy. In one embodiment, the compound of the present invention andthe additional therapeutically active agent are administered in a mannerthat they are active in vivo during overlapping time periods, forexample, have time-period overlapping Cmax, Tmax, AUC or otherpharmacokinetic parameter. In another embodiment, the compound of thepresent invention and the additional therapeutically active agent areadministered to a host in need thereof that do not have overlappingpharmacokinetic parameter, however, one has a therapeutic impact on thetherapeutic efficacy of the other.

In one aspect of this embodiment, the additional therapeutically activeagent is an immune modulator, including but not limited to a checkpointinhibitor, including as non-limiting examples, a PD-1 inhibitor, PD-L 1inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3inhibitor, V-domain Ig suppressor of T-cell activation (VISTA)inhibitors, small molecule, peptide, nucleotide, or other inhibitor. Incertain aspects, the immune modulator is an antibody, such as amonoclonal antibody.

PD-1 inhibitors that blocks the interaction of PD-1 and PD-L1 by bindingto the PD-1 receptor, and in turn inhibit immune suppression include,for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab,AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680(AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1(Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042(Tesaro), and the PD-L1/VISTA inhibitor CA-170 (Curis Inc.). PD-L1inhibitors that block the interaction of PD-1 and PD-L1 by binding tothe PD-L1 receptor, and in turn inhibits immune suppression, include forexample, atezolizumab (Tecentriq), durvalumab (AstraZeneca andMedImmune), KNO35 (Alphamab), and BMS-936559 (Bristol-Myers Squibb).CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibits immunesuppression include, but are not limited to, ipilimumab, tremelimumab(AstraZeneca and MedImmune), AGEN1884 and AGEN2041 (Agenus). LAG-3checkpoint inhibitors, include, but are not limited to, BMS-986016(Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (PrimaBioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013(MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro). Inone embodiment, the PD-1 inhibitor is BGB-A317. In one embodiment, thePD-L1 inhibitor is MED14736. In one embodiment, the PD-L2 inhibitor isrHIgM12B7A.

In one embodiment, the checkpoint inhibitor is a B7 inhibitor, forexample a B7-H3 inhibitor or a B7-H4 inhibitor. In one embodiment, theB7-H3 inhibitor is MGA271.

In one embodiment, the checkpoint inhibitor is an OX40 agonist. In oneembodiment, the checkpoint inhibitor is an anti-OX40 antibody, forexample anti-OX-40 or MEDI6469.

In one embodiment, the checkpoint inhibitor is a GITR agonist. In oneembodiment, the GITR agonist is an anti-GITR antibody, for exampleTRX518.

In one embodiment, the checkpoint inhibitor is a CD137 agonist. In oneembodiment, the CD137 agonist is an anti-CD137 antibody, for examplePF-05082566.

In one embodiment, the checkpoint inhibitor is a CD40 agonist. In oneembodiment, the CD40 agonist is an anti-CD40 antibody, for exampleCF-870,893.

In one embodiment, the checkpoint inhibitor is an IDO inhibitor, forexample INCB24360 or indoximod.

In another embodiment, an active compounds described herein can beadministered in an effective amount for the treatment of abnormal tissueof the male reproductive system such as prostate or testicular cancer,in combination or alternation with an effective amount of an androgen(such as testosterone) inhibitor including but not limited to aselective androgen receptor modulator, a selective androgen receptordegrader, a complete androgen receptor degrader, or another form ofpartial or complete androgen antagonist. In one embodiment, the prostateor testicular cancer is androgen-resistant. Non-limiting examples ofanti-androgen compounds are provided in WO 2011/156518 and U.S. Pat.Nos. 8,455,534 and 8,299,112. Additional non-limiting examples ofanti-androgen compounds include: enzalutamide, apalutamide, cyproteroneacetate, chlormadinone acetate, spironolactone, canrenone, drospirenone,ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

In one embodiment, the additional therapeutically active agent is an ALKinhibitor. Examples of ALK inhibitors include but are not limited toCrizotinib, Alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A,AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113.

In one embodiment, the additional therapeutically active agent is anEGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva),gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686),osimertinib (Tagrisso), olmutinib (Olita), naquotinib (ASP8273),nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009),neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib(TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647;KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib(PF-00299804; Pfizer).

In one embodiment, the additional therapeutically active agent is anHER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab,lapatinib, ado-trastuzumab emtansine, and pertuzumab.

In one embodiment, the additional therapeutically active agent is a CD20inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab,fatumumab, ibritumomab, tositumomab, and ocrelizumab.

In one embodiment, the additional therapeutically active agent is a JAK3inhibitor. Examples of JAK3 inhibitors include tasocitinib.

In one embodiment, the additional therapeutically active agent is aBCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax,ABT-199(4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide),ABT-737(4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide)(navitoclax), ABT-263((R)-4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide),GX15-070 (obatoclax mesylate,(2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole;methanesulfonic acid))), 2-methoxy-antimycin A3, YC137(4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester),pogosin, ethyl2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate,Nilotinib-d3, TW-37(N-[4-[[2-(1,1-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide),Apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, orG3139 (Oblimersen).

In one embodiment, the additional therapeutically active agent is akinase inhibitor. In one embodiment, the kinase inhibitor is selectedfrom a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosinekinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, ora combination thereof.

Examples of PI3 kinase inhibitors include but are not limited toWortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib,Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib,GS-9820, BKM120, GDC-0032 (Taselisib)(2-[4-[2-(2-Isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide),MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate; orMethyl(oxo) {[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719((2S)—N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide),GSK2126458(2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide)(omipalisib), TGX-221((±)-7-Methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one),GSK2636771(2-Methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylicacid dihydrochloride), KIN-193((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoicacid), TGR-1202/RP5264, GS-9820((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one),GS-1101(5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one),AMG-319, GSK-2269557, SAR245409(N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4methylbenzamide), BAY80-6946(2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz),AS 252424(5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione),CZ 24832(5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide),Buparlisib(5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine),GDC-0941(2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine),GDC-0980((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)),SF1126((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecan-18-oate),PF-05212384(N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N′-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea)(gedatolisib), LY3023414, BEZ235(2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile)(dactolisib), XL-765(N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide),and GSK1059615(5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione),PX886([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate(also known as sonolisib)), LY294002, AZD8186, PF-4989216, pilaralisib,GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343),CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240,BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114,TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90,PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850,apitolisib (GDC-0980; RG7422), and the structure described inWO2014/071109.

Examples of BTK inhibitors include ibrutinib (also known asPCI-32765)(Imbruvica™)(1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one),dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292(N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011/0117073,incorporated herein in its entirety), Dasatinib([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide],LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-ibromophenyl)propenamide), GDC-0834([R—N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide],CGI-5604-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide,CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide),CNX-774(4-(4-((4-(3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide),CTA056(7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one),GDC-0834((R)—N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide),GDC-0837((R)—N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide),HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamidehydrochloride), QL-47(1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one),and RN486(6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one),and other molecules capable of inhibiting BTK activity, for examplethose BTK inhibitors disclosed in Akinleye et ah, Journal of Hematology& Oncology, 2013, 6:59, the entirety of which is incorporated herein byreference.

Syk inhibitors include, for example, Cerdulatinib(4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide),entospletinib(6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine),fostamatinib([6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyldihydrogen phosphate), fostamatinib disodium salt (sodium(6-(5-fluoro-2-(3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methylphosphate), BAY 61-3606(2-(7-(3,4-Dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamideHCl), R09021(6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylicacid amide), imatinib (Gleevac;4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide),staurosporine, GSK143(2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide),PP2(1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine),PRT-060318(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide),PRT-062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamidehydrochloride), R112(3,3′-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348(3-Ethyl-4-methylpyridine), R406(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one), piceatannol (3-Hydroxyresveratol), YM193306(see Singh et al.Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J.Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (seeSingh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), Compound D (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), PRT060318 (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), luteolin (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), apigenin (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), quercetin (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), fisetin (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), myricetin (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), morin (see Singh et al.Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J.Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein).

In one embodiment, the additional therapeutically active agent is a MEKinhibitor. MEK inhibitors are well known, and include, for example,trametinib/GSK1120212(N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide),selumetinib(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide),pimasertib/AS703026NISC 1935369((S)—N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide),XL-518/GDC-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol),refametinib/BAY869766/RDEA1 19(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide),PD-0325901(N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide),TAK733((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione),MEK162/ARRY438162(5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide),R05126766 (3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one),WX-554, R04987655/CH4987655(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide),or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide),U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib,PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088.

In one embodiment, the additional therapeutically active agent is a Rafinhibitor. Raf inhibitors are known and include, for example,Vemurafinib(N-[3-[[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide),sorafenib tosylate(4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide;4-methylbenzenesulfonate),AZ628(3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide),NVP-BHG712(4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide),RAF-265(1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine),2-Bromoaldisine(2-Bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf KinaseInhibitor IV(2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol),Sorafenib N-Oxide(4-[4-[[[[4-Chloro-3(trifluoroMethyl)phenyl]aMino]carbonyl]aMino]phenoxy]-N-Methyl-2pyridinecarboxaMide1-Oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628,SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818(Encorafenib).

In one embodiment, the additional therapeutically active agent is an AKTinhibitor, including but not limited to, MK-2206, GSK690693, Perifosine,(KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, andMiltefosine, a FLT-3 inhibitor, including but not limited to, P406,Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib(MLN518), ENMD-2076, and KW-2449, or a combination thereof.

In one embodiment, the additional therapeutically active agent is anmTOR inhibitor. Examples of mTOR inhibitors include but are not limitedto rapamycin and its analogs, everolimus (Afinitor), temsirolimus,ridaforolimus, sirolimus, and deforolimus. Examples of MEK inhibitorsinclude but are not limited to tametinib/GSK1120212(N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide),selumetinob(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide),pimasertib/AS703026NISC1935369((S)—N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide),XL-518/GDC-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol)(cobimetinib), refametinib/BAY869766/RDEA119(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide),PD-0325901(N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide),TAK733((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione),MEK162/ARRY438162(5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6carboxamide), R05126766 (3-[[3-Fluoro-2-(methyl sulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one),WX-554, R04987655/CH4987655(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide), or AZD8330(2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).

In one embodiment, the additional therapeutically active agent is a RASinhibitor. Examples of RAS inhibitors include but are not limited toReolysin and siG12D LODER.

In one embodiment, the additional therapeutically active agent is a HSPinhibitor. HSP inhibitors include but are not limited to Geldanamycin or17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol.

Additional bioactive compounds include, for example, everolimus,trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693,RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258,GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054,PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, anaurora kinase inhibitor, a PIK-1 modulator, an HDAC inhibitor, a c-METinhibitor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, ananti-HGF antibody, a focal adhesion kinase inhibitor, a Map kinasekinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, panitumumab,amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin,ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan,tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111,131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan,IL13-PE38QQR, INO 1001, IPdR₁ KRX-0402, lucanthone, LY317615, neuradiab,vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin,ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide,gemcitabine, doxorubicin, liposomal doxorubicin,5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,di sodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole,DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258);3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib,AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelinpamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate,megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide,megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib,canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016,Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248,sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide,L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil,cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine,dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-freepaclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705,droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene,fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339,ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin,40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonist,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin,epoetin alfa, darbepoetin alfa and mixtures thereof.

In one embodiment, the additional therapeutically active agent isselected from, but are not limited to, Imatinib mesylate (Gleevac®),Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®),Trastuzumab (Herceptin®), trastuzumab-DM1, Pertuzumab (Perjeta™),Lapatinib (Tykerb®), Gefitinib (Iressa®), Erlotinib (Tarceva®),Cetuximab (Erbitux®), Panitumumab (Vectibix®), Vandetanib (Caprelsa®),Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®),Bexarotene (Tagretin®), Alitretinoin (Panretin®), Tretinoin (Vesanoid®),Carfilizomib (Kyprolis™), Pralatrexate (Folotyn®), Bevacizumab(Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib(Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), andCabozantinib (Cometriq™).

In certain aspects, the additional therapeutically active agent is ananti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic,an additional therapeutic agent, or an immunosuppressive agent.

Suitable chemotherapeutic additional therapeutically active agent sinclude, but are not limited to, a radioactive molecule, a toxin, alsoreferred to as cytotoxin or cytotoxic agent, which includes any agentthat is detrimental to the viability of cells, and liposomes or othervesicles containing chemotherapeutic compounds. General anticancerpharmaceutical agents include: Vincristine (Oncovin®) or liposomalvincristine (Marqibo®), Daunorubicin (daunomycin or Cerubidine®) ordoxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara-C, orCytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargaseor Oncaspar®), Etoposide (VP-16), Teniposide (Vumon®), 6-mercaptopurine(6-MP or Purinethol®), Methotrexate, Cyclophosphamide (Cytoxan®),Prednisone, Dexamethasone (Decadron), imatinib (Gleevec®), dasatinib(Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib(Iclusig™). Examples of additional suitable chemotherapeutic agentsinclude but are not limited to 1-dehydrotestosterone, 5-fluorouracildecarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin,aldesleukin, an alkylating agent, allopurinol sodium, altretamine,amifostine, anastrozole, anthramycin (AMC)), an anti-mitotic agent,cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloroplatinum, anthracycline, an antibiotic, an antimetabolite, asparaginase,BCG live (intravesical), betamethasone sodium phosphate andbetamethasone acetate, bicalutamide, bleomycin sulfate, busulfan,calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine(CCNU), carmustine (BSNU), Chlorambucil, Cisplatin, Cladribine,Colchicin, conjugated estrogens, Cyclophosphamide, Cyclothosphamide,Cytarabine, Cytarabine, cytochalasin B, Cytoxan, Dacarbazine,Dactinomycin, dactinomycin (formerly actinomycin), daunirubicin HCL,daunorucbicin citrate, denileukin diftitox, Dexrazoxane,Dibromomannitol, dihydroxy anthracin dione, Docetaxel, dolasetronmesylate, doxorubicin HCL, dronabinol, E. coli L-asparaginase, emetine,epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol,estramustine phosphate sodium, ethidium bromide, ethinyl estradiol,etidronate, etoposide citrororum factor, etoposide phosphate,filgrastim, floxuridine, fluconazole, fludarabine phosphate,fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids,goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea,idarubicin HCL, ifosfamide, interferon α-2b, irinotecan HCL, letrozole,leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine,lomustine, maytansinoid, mechlorethamine HCL, medroxyprogesteroneacetate, megestrol acetate, melphalan HCL, mercaptipurine, mesna,methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane,mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL,paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL,plimycin, polifeprosan 20 with carmustine implant, porfimer sodium,procaine, procarbazine HCL, propranolol, rituximab, sargramostim,streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone,tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL,toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastinesulfate, vincristine sulfate, and vinorelbine tartrate.

Additional therapeutic agents that can be administered in combinationwith a Degrader disclosed herein can include bevacizumab, sutinib,sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib,vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522),cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab,dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine,atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab,dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib,carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir,nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat,mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin,talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib,dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib,bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991,ribociclib (LEE011), amebaciclib (LY2835219), HDM201, fulvestrant(Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398,necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

In one embodiment, the additional therapy is a monoclonal antibody(MAb). Some MAbs stimulate an immune response that destroys cancercells. Similar to the antibodies produced naturally by B cells, theseMAbs may “coat” the cancer cell surface, triggering its destruction bythe immune system. For example, bevacizumab targets vascular endothelialgrowth factor(VEGF), a protein secreted by tumor cells and other cellsin the tumor's microenvironment that promotes the development of tumorblood vessels. When bound to bevacizumab, VEGF cannot interact with itscellular receptor, preventing the signaling that leads to the growth ofnew blood vessels. Similarly, cetuximab and panitumumab target theepidermal growth factor receptor (EGFR), and trastuzumab targets thehuman epidermal growth factor receptor 2 (HER-2). MAbs that bind to cellsurface growth factor receptors prevent the targeted receptors fromsending their normal growth-promoting signals. They may also triggerapoptosis and activate the immune system to destroy tumor cells.

In one aspect of the present invention, the additional therapeuticallyactive agent is an immunosuppressive agent. The immunosuppressive agentcan be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g.Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTORinhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus(RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus,biolimus-7, biolimus-9, a rapalog, e.g. ridaforolimus, azathioprine,campath 1H, a S1P receptor modulator, e.g. fingolimod or an analoguethereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof,e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil(CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®,THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1,15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig,anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®),mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981(pimecrolimus, Elidel®), CTLA41g (Abatacept), belatacept, LFA31getanercept (sold as Enbrel® by Immunex), adalimumab (Humira®),infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®),Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab,Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate,benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin,aspirin and ibuprofen.

In one embodiment, the additional therapy is bendamustine. In oneembodiment, the additional therapy is obinutuzmab. In one embodiment,the additional therapy is a proteasome inhibitor, for example ixazomibor oprozomib. In one embodiment, the additional therapy is a histonedeacetylase inhibitor, for example ACY241. In one embodiment, theadditional therapy is a BET inhibitor, for example GSK525762A, OTX015,BMS-986158, TEN-010, CPI-0610, INCB54329, BAY1238097, FT-1101, ABBV-075,BI 894999, GS-5829, GSK1210151A (I-BET-151), CPI-203, RVX-208, XD46,MS436, PFI-1, RVX2135, ZEN3365, XD14, ARV-771, MZ-1, PLX5117,4-[2-(cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one,EP11313 and EP11336. In one embodiment, the additional therapy is anMCL-1 inhibitor, for example AZD5991, AMG176, MIK665, S64315, or S63845.In one embodiment, the additional therapy is an LSD-1 inhibitor, forexample ORY-1001, ORY-2001, INCB-59872, IMG-7289, TAK-418, GSK-2879552,4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluoro-benzonitrileor a salt thereof. In one embodiment, the additional therapy is a CS1antibody, for example elotuzumab. In one embodiment, the additionaltherapy is a CD38 antibody, for example daratumumab or isatuximab. Inone embodiment, the additional therapy is a BCMA antibody orantibody-conjugate, for example GSK2857916 or BI 836909.

In some embodiments, a degrader described herein is administered incombination or alternation with one or more cellular immunotherapeutics.In some embodiments, the cellular immunotherapeutic is an engineeredimmune cell. Engineered immune cells include, for example, but are notlimited to, engineered T-cell receptor (TCR) cells and engineeredchimeric antigen receptor (CAR) cells. Engineered T Cell Receptor (TCR)Therapy generally involves the introduction of an engineered T cellreceptor targeting specific cancer antigens into a patient or donorderived immune effector cell, for example a T-cell or natural killercell. Alternatively, Chimeric Antigen Receptor (CAR) Therapy generallyinvolves the introduction of a chimeric antigen receptor targeting aspecific cancer antigen into a patient or donor derived immune effectorcell, for example a T-cell, natural killer cells, or macrophage. One keyadvantage of CARs compared to TCRs is their ability to bind to cancercells even if their antigens aren't presented on the surface via MHC,which can render more cancer cells vulnerable to their attacks. However,CAR cells can only recognize antigens that themselves are naturallyexpressed on the cell surface, so the range of potential antigen targetsis smaller than with TCRs.

In some embodiments, the immunotherapeutic is an engineered TCR or CARimmune cell, wherein the TCR or CAR targets one or more tumor associatedantigens selected from: BCMA, an important signaling receptor foundnaturally on mature B cells; often expressed by lymphoma and myelomacells; CD19, a receptor found on the surface of almost all B cells thatinfluences their growth, development, and activity, often expressed byleukemia, lymphoma, and myeloma cells; CD22, a receptor found primarilyon the surface of mature B cells; often expressed by leukemia andlymphoma cells; CD30, a receptor that is expressed on certain types ofactivated immune cells, often expressed by leukemia and lymphoma cells;CD33: a surface receptor found on several types of immune cells; oftenexpressed by leukemia cells; CD56, a protein found on both neurons andnatural killer immune cells; CD123 (also known as IL-3R), a receptorfound on immune cells that is involved in proliferation anddifferentiation, and often expressed by leukemia and lymphoma cells;CEA, a protein involved in cellular adhesion normally produced onlybefore birth, often abnormally expressed in cancer and may contribute tometastasis; EBV-related antigens, foreign viral proteins expressed byEpstein-Barr Virus (EBV)-infected cancer cells; EGFR, a pathway thatcontrols cell growth and is often mutated in cancer; GD2, a pathway thatcontrols cell growth, adhesion, and migration, and is often abnormallyoverexpressed in cancer cells; GPC3, a cell surface protein thought tobe involved in regulating growth and cell division; HER2, a pathway thatcontrols cell growth and is commonly overexpressed in some cancers,particularly breast cancer, and is associated with metastasis;HPV-related antigens, foreign viral proteins expressed by cancer cellsthat develop as a consequence of having been infected with HumanPapilloma Virus (HPV); MAGE antigens, the genes that produce theseproteins are normally turned off in adult cells, but can becomereactivated in cancer cells, flagging them as abnormal to the immunesystem; Mesothelin, a protein that is commonly overexpressed in cancerand may aid metastasis; MUC-1, a sugar-coated protein that is commonlyoverexpressed in cancer; NY-ESO-1, a protein that is normally producedonly before birth, but is often abnormally expressed in cancer; PSCA, asurface protein that is found on several cell types and is oftenoverexpressed by cancer cells; PSMA, a surface protein found on prostatecells that is often overexpressed by prostate cancer cells; ROR1, atyrosine kinase-like orphan receptor that is mostly expressed beforebirth rather than in adult tissues, but is often abnormally expressed incancer and may promote cancer cell metastasis as well as prevent cancercell death; WT1, a protein that promotes cancer progression, isabnormally expressed in patients with cancer, especially leukemia; andClaudin 18.2: a surface protein overexpressed in some esophageal cancersand involved in invasion and survival. In some embodiments, theengineered CAR therapy is Axicabtagene ciloleucel (Yescarta®): aCD19-targeting CAR T cell immunotherapy; approved for subsets ofpatients with lymphoma. In some embodiments, the engineered CAR therapyis Tisagenlecleucel (Kymriah®): a CD19-targeting CAR T cellimmunotherapy; approved for subsets of patients with leukemia andlymphoma. In some embodiments, the engineered CAR therapy isLisocabtagene maraleucel (Bristol-Myers Squibb Co.): a CD19-targetingCAR T cell immunotherapy which is used to treat relapsed/refractorylarge B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL).In some embodiments, the engineered CAR Therapy is a BCMA CAR-T therapy,for example, but not limited to JNJ-4528 (Johnson & Johnson) andKITE-585 (Gilead). In some embodiments, the engineered CAR-T therapy isa dual specific CAR-T targeting BCMA and CD38. In some embodiments, theengineered CAR therapy is a CD20/CD22 dual targeted CAR-T cell therapy.Compositions and methods for deriving CAR immune cells are described,for example, in U.S. Pat. No. 5,359,046 (Cell Genesys); U.S. Pat. No.5,712,149 (Cell Genesys); U.S. Pat. No. 6,103,521 (Cell Genesys); U.S.Pat. No. 7,446,190 (Memorial Sloan Kettering Cancer Center); U.S. Pat.No. 7,446,179 (City of Hope); U.S. Pat. No. 7,638,325 (U. Penn); U.S.Pat. No. 8,911,993 (U. Penn); U.S. Pat. No. 8,399,645 (St. Jude'sChildren's Hospital); U.S. Pat. No. 8,906,682 (U. Penn); U.S. Pat. No.8,916,381 (U. Penn); U.S. Pat. No. 8,975,071 (U. Penn); U.S. Pat. No.9,102,760 (U. Penn); U.S. 94,644 (U. Penn); U.S. Pat. No. 9,855,298(Gilead); U.S. Pat. No. 10,144,770 (St. Jude Children's Hospital); U.S.Pat. No. 10,266,580 (U. Penn); U.S. Pat. No. 10,189,903 (SeattleChildren's Hospital); WO 2014/011988 (U. Penn); WO 2014/145252; WO2014/153270 (Novartis AG); US 2018/0360880 (Memorial Sloan KetteringCancer Center); WO 2017/0243 (Dana Farber Cancer Institute); WO2016/115177 (Juno Therapeutics, Inc.); each of which is incorporatedherein by reference.

In some embodiments, the immunotherapeutic is a non-engineered adoptivecell therapy. Adoptive cell therapy is an approach used to bolster theability of the immune system to fight diseases, such as tumor and viralinfections. According to this approach, immune cells, for example Tcells or NK cells, are collected from a patient or donor, stimulated inthe presence of antigen presenting cells bearing tumor orviral-associated antigens, and then expanded ex vivo. In someembodiments, the adoptive cell therapy is Tumor-Infiltrating Lymphocyte(TIL) Therapy, which harvests naturally occurring T cells that havealready infiltrated patients' tumors, and are then activated andexpanded, Then, and re-infused into patients. In some embodiments, thenon-engineered adoptive cell therapy includes autologous or allogeneicimmune cells, for example αβ T-cells activated to target multiplepotential antigens. One strategy used to develop targeted non-engineeredT-cells involves the ex vivo expansion of T-cells by antigen-specificstimulation of patient-derived (autologous) or donor-derived(allogeneic) T cells ex vivo. These strategies generally involve theisolation of peripheral blood mononuclear cells (PBMCs) and exposure ofthe cells to one or more tumor associated antigens. In particular,approaches to generate multi-antigen specific T-cells have focused onpriming and activating T-cells with multiple targeted antigenoverlapping peptide libraries, for example multiple libraries of 15merpeptides overlapping by 11 amino acids spanning the whole amino acidsequence of several target antigens (see for example commerciallyavailable overlapping peptide library products from JPT Technologies orMiltenyi). Strategies for activating ex vivo autologous or allogenicimmune effector cells for targeting tumor associated antigens aredescribed in, for example: US2011/0182870 (Baylor College of Medicine);US 2015/0010519 (Baylor College of Medicine); US2015/0017723 (BaylorCollege of Medicine); WO2006026746 (United States Government, Departmentof Health and Human Services); US 2015/0044258 (Cell Medica/KurrTherapeutics); WO2016/154112 (Children's National Medical Center); WO2017/203356 (Queensland Institute of Medical Research); WO 2018/005712(Geneius Biotechnology, Inc.); Vera et al. Accelerated Production ofAntigen-Specific T Cells for Pre-clinical and Clinical Applicationsusing Gas-permeable Rapid Expansion Cultureware (G-Rex), April 2010Journal of Immunotherapy 33(3):305-315; Shafer et al. Antigen-specificCytotoxic T Lymphocytes can Target Chemoresistant Side-Population TumorCells in Hodgkin's Lymphoma; May 2010 Leukemia Lymphoma 51(5): 870-880;Quintarelli et al. High Avidity Cytotoxic T Lymphocytes Specific for aNew PRAME-derived Peptide can Target Leukemic and Leukemic-precursorcells, Mar. 24, 2011 Blood 117(12): 3353-3362; Bollard et al.Manufacture of GMP-grade Cytotoxic T Lymphocytes Specific for LMP1 andLMP2 for Patients with EBV-associated Lymphoma, May 2011 Cytotherapy13(5): 518-522; Ramos et al. Human Papillomavirus Type 16 E6/E7-SpecificCytotoxic T Lymphocytes for Adoptive Immunotherapy of HPV-associatedMalignancies, January 2013 Immunotherapy 36(1): 66-76; Weber et al.Generation of tumor antigen-specific T cell lines from pediatricpatients with acute lymphoblastic leukemia implications forimmunotherapy, Clinical Cancer Research 2013 September 15; 19(18):5079-5091; Ngo et al. Complementation of antigen presenting cells togenerate T lymphocytes with broad target specificity, Journal ofImmunotherapy. 2014 May; 37(4): 193-203; each of which is incorporatedherein by reference. In some embodiments, the non-engineered, activatedimmune cell administered in combination or alternation with a degradercomposition described herein is selected from activated CD4+ T-cells(T-helper cells), CD8+ T-cells (Cytotoxic T-Lymphocytes), CD3+/CD56+Natural Killer T-cells (CD3+ NKT), and γδ T-cells (γδ T-cells), orcombinations thereof. In some embodiments, the adoptive cell therapy isa composition comprising CD4+ T-cells (T-helper cells). In someembodiments, the adoptive cell therapy is a composition comprising CD8+T-cells (Cytotoxic T-Lymphocytes). In some embodiments, the adoptivecell therapy is a composition comprising CD3+/CD56+ Natural KillerT-cells (CD3+ NKT). In some embodiments, the adoptive cell therapy is acomposition comprising CD4+ T-cells (T-helper cells), CD8+ T-cells(Cytotoxic T-Lymphocytes), CD3+/CD56+ Natural Killer T-cells (CD3+ NKT),and γδ T-cells (γδ T-cells).

In some embodiments, the immunotherapy is a bi-specific T-cell engager(BiTE). A bi-specific T-cell engager directs T-cells to target and bindwith a specific antigen on the surface of a cancer cell. For example,Blinatumomab (Amgen), a BiTE has recently been approved as a second linetherapy in Philadelphia chromosome-negative relapsed or refractory acutelymphoblastic leukemia. Blinatumomab is given by continuous intravenousinfusion in 4-week cycles.

In certain embodiments, the additional therapeutically active agent isan additional inhibitor of Ikaros (“IKZF1”) and/or Aiolos (“IKZF3”). Inanother embodiment, the additional therapeutically active agent is aninhibitor of Helios (“IKZF2”). In another embodiment, the additionaltherapeutically active agent is an inhibitor of Eos (“IKZF4”). Inanother embodiment, the additional therapeutically active agent is aninhibitor of Pegasus (“IKZF5”). In another embodiment, the additionaltherapeutically active agent is a cereblon ligand.

Non-limiting examples of cereblon ligands that may be used incombination with a compound of the present invention include:thalidomide, lenalidomide, pomalidomide, and iberdomide.

In another embodiment the additional compound that may be used incombination with a compound of the present invention is selected fromthose described in WO2012/175481, WO2015/085172, WO2015/085172,WO2017/067530, WO2017/121388, WO2017/201069, WO2018/108147,WO2018/118947, WO2019/038717, WO2019/191112, WO2020/006233,WO2020/006262, WO2020/006265, or WO2020/012334.

In another embodiment the additional compound that may be used incombination with a compound of the present invention is selected fromthose described in WO2019/060693, WO2019/060742, WO2019/133531,WO2019/140380, WO2019/140387, WO2010/010177, WO2020/010210, orWO2020/010227.

In another embodiment the additional compound that may be used incombination with a compound of the present invention is selected fromthose described in WO2015/160845, WO2016/118666, WO2016/149668,WO2016/197032, WO2016/197114, WO2017/011371, WO2017/0115901,WO2017/030814, WO2017/176708, WO2018/053354, WO2018/0716060,WO2018/102067, WO2018/118598, WO2018/119357, WO2018/119441,WO2018/119448, WO2018/140809, WO2018/226542, WO2019/023553,WO2019/099926, WO2019/195201, WO2019/195609, WO2019/199816,WO2020/023851, WO2020/041331, or WO2020/051564.

In another embodiment the additional compound that may be used incombination with a compound of the present invention is selected fromthose described in WO2016/105518, WO2017/007612, WO2017/024317,WO2017/024318, WO2017/024319, WO2017/117473, WO2017/117474,WO2017/185036, WO2018/064589, WO2018/148440, WO2018/148443,WO2018/226978, WO2019/014429, WO2019/079701, WO2019/094718,WO2019/094955, WO2019/118893, WO2019/165229, WO2020/006262,WO2020/018788, WO2020/069105, WO2020/069117, or WO2020/069125.

In another embodiment the additional compound that may be used incombination with a compound of the present invention is selected fromthose described in WO2017/197036, WO2017/197046, WO2017/197051,WO2017/197055, WO2017/197056, WO 2017/115218, WO2018/220149,WO2018/237026, WO2019/099868, WO2019/121562, WO2019/149922,WO2019/191112, WO2019/204354, WO2019/236483, or WO2020/051235.

V. Pharmaceutical Compositions

Any of the compounds as disclosed herein can be administered as the neatchemical, but are more typically administered as a pharmaceuticalcomposition, that includes an effective amount for a host, typically ahuman, in need of such treatment for any of the disorders describedherein. Accordingly, the disclosure provides pharmaceutical compositionscomprising an effective amount of compound or pharmaceuticallyacceptable salt together with at least one pharmaceutically acceptablecarrier for any of the uses described herein. The pharmaceuticalcomposition may contain a compound or salt as the only active agent, or,in an alternative embodiment, the compound and at least one additionalactive agent.

In certain embodiments the pharmaceutical composition is in a dosageform that contains from about 0.0005 mg to about 2000 mg, from about0.001 mg to about 1000 mg, from about 0.001 mg to about 600 mg, or fromabout 0.001 mg to about 1, 5, 10, 15, 20, 25, 50, 100, 200 or 300 mg mgof the active compound. In another embodiment the pharmaceuticalcomposition is in a dosage form that contains from about 0.01 mg toabout 1, 5, 10, 15, 20, 25, 50 or 100 mg, from about 0.05 mg to about 1,5, 10, 15, 20, 25, 50 or 100 mg, from about 0.1 mg to about 1, 5, 10,15, 20, 25 or 50 mg, from about 0.02 mg to about 1, 5, 10, 15, 20, 25 or50 mg of the active compound, from about 0.5 mg to about 1, 5, 10, 15,20, 25 or 50 mg. In another embodiment the pharmaceutical composition isin a dosage form that contains from about 0.01 mg to about 10 mg, fromabout 0.05 mg to about 8 mg, or from about 0.05 mg to about 6 mg, orfrom about 0.05 mg to about 5 mg of the active compound. In anotherembodiment the pharmaceutical composition is in a dosage form thatcontains from about 0.1 mg to about 10 mg, from about 0.5 mg to about 8mg, or from about 0.5 mg to about 6 mg, or from about 0.5 mg to about 5mg of the active compound. Nonlimiting examples are dosage forms with atleast about 0.0005, 0.001, 0.01, 0.1, 1, 2.5, 5, 10, 25, 50, 100, 200,250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt.Alternative nonlimiting examples are dosage forms with not greater thanabout 0.01, 0.1, 1, 2.5, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500,600, 700, or 750 mg of active compound, or its salt.

The pharmaceutical composition may also include a molar ratio of theactive compound and an additional therapeutically active agent. Innon-limiting illustrative embodiments the pharmaceutical composition maycontain a molar ratio of about up to 0.5:1, about up to 1:1, about up to2:1, about up to 3:1 or from about up to 1.5:1 to about up to 4:1 of ananti-inflammatory or immunosuppressing agent to the compound of thepresent invention. Compounds disclosed herein may be administeredorally, topically, parenterally, by inhalation or spray, sublingually,via implant, including ocular implant, transdermally, via buccaladministration, rectally, as an ophthalmic solution, injection,including ocular injection, intravenous, intra-aortal, intracranial,subdermal, intraperitoneal, subcutaneous, transnasal, sublingual, orrectal or by other means, in dosage unit formulations containingconventional pharmaceutically acceptable carriers. For ocular delivery,the compound can be administered, as desired, for example, viaintravitreal, intrastromal, intracameral, sub-tenon, sub-retinal,retro-bulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival,episcleral, periocular, transscleral, retrobulbar, posteriorjuxtascleral, circumcorneal, or tear duct injections, or through amucus, mucin, or a mucosal barrier, in an immediate or controlledrelease fashion or via an ocular device.

The pharmaceutical composition may be formulated as any pharmaceuticallyuseful form, e.g., as an aerosol, a cream, a gel, a pill, an injectionor infusion solution, a capsule, a tablet, a syrup, a transdermal patch,a subcutaneous patch, a dry powder, an inhalation formulation, in amedical device, suppository, buccal, or sublingual formulation,parenteral formulation, or an ophthalmic solution. Some dosage forms,such as tablets and capsules, are subdivided into suitably sized unitdoses containing appropriate quantities of the active components, e.g.,an effective amount to achieve the desired purpose.

Carriers include excipients and diluents and must be of sufficientlyhigh purity and sufficiently low toxicity to render them suitable foradministration to the patient being treated. The carrier can be inert orit can possess pharmaceutical benefits of its own. The amount of carrieremployed in conjunction with the compound is sufficient to provide apractical quantity of material for administration per unit dose of thecompound.

Classes of carriers include, but are not limited to binders, bufferingagents, coloring agents, diluents, disintegrants, emulsifiers,flavorants, glidents, lubricants, preservatives, stabilizers,surfactants, tableting agents, and wetting agents. Some carriers may belisted in more than one class, for example vegetable oil may be used asa lubricant in some formulations and a diluent in others.Pharmaceutically acceptable carriers are carriers that do not cause anysevere adverse reactions in the human body when dosed in the amount thatwould be used in the corresponding pharmaceutical composition. Exemplarypharmaceutically acceptable carriers include sugars, starches,celluloses, powdered tragacanth, malt, gelatin; talc, and vegetableoils. Optional active agents may be included in a pharmaceuticalcomposition, which do not substantially interfere with the activity ofthe compound of the present invention.

The pharmaceutical compositions/combinations can be formulated for oraladministration. These compositions can contain any amount of activecompound that achieves the desired result, for example between 0.1 and99 weight % (wt. %) of the compound including for example at least about5 wt. % of the compound. Some embodiments contain from about 25 wt. % toabout 50 wt. % or from about 5 wt. % to about 75 wt. % of the compound.

Formulations suitable for rectal administration are typically presentedas unit dose suppositories. These may be prepared by admixing the activecompound with one or more conventional solid carriers, for example,cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin preferablytake the form of an ointment, cream, lotion, paste, gel, spray, aerosol,or oil. Carriers which may be used include petroleum jelly, lanoline,polyethylene glycols, alcohols, transdermal enhancers, and combinationsof two or more thereof.

Formulations suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Formulationssuitable for transdermal administration may also be delivered byiontophoresis (see, for example, Pharmaceutical Research 3 (6):318(1986)) and typically take the form of an optionally buffered aqueoussolution of the active compound. In one embodiment, microneedle patchesor devices are provided for delivery of drugs across or into biologicaltissue, particularly the skin. The microneedle patches or devices permitdrug delivery at clinically relevant rates across or into skin or othertissue barriers, with minimal or no damage, pain, or irritation to thetissue.

Formulations suitable for administration to the lungs can be deliveredby a wide range of passive breath driven and active power drivensingle/-multiple dose dry powder inhalers (DPI). The devices mostcommonly used for respiratory delivery include nebulizers, metered-doseinhalers, and dry powder inhalers. Several types of nebulizers areavailable, including jet nebulizers, ultrasonic nebulizers, andvibrating mesh nebulizers. Selection of a suitable lung delivery devicedepends on parameters, such as nature of the drug and its formulation,the site of action, and pathophysiology of the lung.

Many methods and devices for drug delivery are known in the art.Non-limiting examples are described in the following patents and patentapplications (fully incorporated herein by reference). Examples are U.S.Pat. No. 8,192,408 titled “Ocular trocar assembly” (Psivida Us, Inc.);U.S. Pat. No. 7,585,517 titled “Transcleral delivery” (Macusight, Inc.);U.S. Pat. Nos. 5,710,182 and 5,795,913 titled “Ophthalmic composition”(Santen OY); U.S. Pat. No. 8,663,639 titled “Formulations for treatingocular diseases and conditions”, U.S. Pat. No. 8,486,960 titled“Formulations and methods for vascular permeability-related diseases orconditions”, U.S. Pat. Nos. 8,367,097 and 8,927,005 titled “Liquidformulations for treatment of diseases or conditions”, U.S. Pat. No.7,455,855 titled “Delivering substance and drug delivery system usingthe same” (Santen Pharmaceutical Co., Ltd.); WO/2011/050365 titled“Conformable Therapeutic Shield For Vision and Pain” and WO/2009/145842titled “Therapeutic Device for Pain Management and Vision” (ForsightLabs, LLC); U.S. Pat. Nos. 9,066,779 and 8,623,395 titled “Implantabletherapeutic device”, WO/2014/160884 titled “Ophthalmic Implant forDelivering Therapeutic Substances”, U.S. Pat. Nos. 8,399,006, 8,277,830,8,795,712, 8,808,727, 8,298,578, and WO/2010/088548 titled “Posteriorsegment drug delivery”, WO/2014/152959 and US20140276482 titled “Systemsfor Sustained Intraocular Delivery of Low Solubility Compounds from aPort Delivery System Implant”, U.S. Pat. Nos. 8,905,963 and 9,033,911titled “Injector apparatus and method for drug delivery”, WO/2015/057554titled “Formulations and Methods for Increasing or Reducing Mucus”, U.S.Pat. Nos. 8,715,712 and 8,939,948 titled “Ocular insert apparatus andmethods”, WO/2013/116061 titled “Insertion and Removal Methods andApparatus for Therapeutic Devices”, WO/2014/066775 titled “OphthalmicSystem for Sustained Release of Drug to the Eye”, WO/2015/085234 andWO/2012/019176 titled “Implantable Therapeutic Device”, WO/2012/065006titled “Methods and Apparatus to determine Porous Structures for DrugDelivery”, WO/2010/141729 titled “Anterior Segment Drug Delivery”,WO/2011/050327 titled “Corneal Denervation for Treatment of OcularPain”, WO/2013/022801 titled “Small Molecule Delivery with ImplantableTherapeutic Device”, WO/2012/019047 titled “Subconjunctival Implant forPosterior Segment Drug Delivery”, WO/2012/068549 titled “TherapeuticAgent Formulations for Implanted Devices”, WO/2012/019139 titled“Combined Delivery Methods and Apparatus”, WO/2013/040426 titled “OcularInsert Apparatus and Methods”, WO/2012/019136 titled “Injector Apparatusand Method for Drug Delivery”, WO/2013/040247 titled “Fluid ExchangeApparatus and Methods” (ForSight Vision4, Inc.); US/2014/0352690 titled“Inhalation Device with Feedback System”, U.S. Pat. No. 8,910,625 andUS/2015/0165137 titled “Inhalation Device for Use in Aerosol Therapy”(Vectura GmbH); U.S. Pat. No. 6,948,496 titled “Inhalers”,US/2005/0152849 titled “Powders comprising anti-adherent materials foruse in dry powder inhalers”, U.S. Pat. Nos. 6,582,678, 8,137,657,US/2003/0202944, and US/2010/0330188 titled “Carrier particles for usein dry powder inhalers”, U.S. Pat. No. 6,221,338 titled “Method ofproducing particles for use in dry powder inhalers”, U.S. Pat. No.6,989,155 titled “Powders”, US/2007/0043030 titled “Pharmaceuticalcompositions for treating premature ejaculation by pulmonaryinhalation”, U.S. Pat. No. 7,845,349 titled “Inhaler”, US/2012/0114709and U.S. Pat. No. 8,101,160 titled “Formulations for Use in InhalerDevices”, US/2013/0287854 titled “Compositions and Uses”,US/2014/0037737 and U.S. Pat. No. 8,580,306 titled “Particles for Use ina Pharmaceutical Composition”, US/2015/0174343 titled “Mixing Channelfor an Inhalation Device”, U.S. Pat. No. 7,744,855 and US/2010/0285142titled “Method of making particles for use in a pharmaceuticalcomposition”, U.S. Pat. No. 7,541,022, US/2009/0269412, andUS/2015/0050350 titled “Pharmaceutical formulations for dry powderinhalers” (Vectura Limited).

Additional non-limiting examples of how to deliver the active compoundsare provided in WO/2015/085251 titled “Intracameral Implant forTreatment of an Ocular Condition” (Envisia Therapeutics, Inc.);WO/2011/008737 titled “Engineered Aerosol Particles, and AssociatedMethods”, WO/2013/082111 titled “Geometrically Engineered Particles andMethods for Modulating Macrophage or Immune Responses”, WO/2009/132265titled “Degradable compounds and methods of use thereof, particularlywith particle replication in non-wetting templates”, WO/2010/099321titled “Interventional drug delivery system and associated methods”,WO/2008/100304 titled “Polymer particle composite having high fidelityorder, size, and shape particles”, WO/2007/024323 titled “Nanoparticlefabrication methods, systems, and materials” (Liquidia Technologies,Inc. and the University of North Carolina at Chapel Hill);WO/2010/009087 titled “Iontophoretic Delivery of a Controlled-ReleaseFormulation in the Eye”, (Liquidia Technologies, Inc. and EyegatePharmaceuticals, Inc.) and WO/2009/132206 titled “Compositions andMethods for Intracellular Delivery and Release of Cargo”, WO/2007/133808titled “Nano-particles for cosmetic applications”, WO/2007/056561 titled“Medical device, materials, and methods”, WO/2010/065748 titled “Methodfor producing patterned materials”, WO/2007/081876 titled“Nanostructured surfaces for biomedical/biomaterial applications andprocesses thereof” (Liquidia Technologies, Inc.).

Additional non-limiting examples of drug delivery devices and methodsinclude, for example, US20090203709 titled “Pharmaceutical Dosage FormFor Oral Administration Of Tyrosine Kinase Inhibitor” (AbbottLaboratories); US20050009910 titled “Delivery of an active drug to theposterior part of the eye via subconjunctival or periocular delivery ofa prodrug”, US 20130071349 titled “Biodegradable polymers for loweringintraocular pressure”, U.S. Pat. No. 8,481,069 titled “Tyrosine kinasemicrospheres”, U.S. Pat. No. 8,465,778 titled “Method of making tyrosinekinase microspheres”, U.S. Pat. No. 8,409,607 titled “Sustained releaseintraocular implants containing tyrosine kinase inhibitors and relatedmethods”, U.S. Pat. No. 8,512,738 and US 2014/0031408 titled“Biodegradable intravitreal tyrosine kinase implants”, US 2014/0294986titled “Microsphere Drug Delivery System for Sustained IntraocularRelease”, U.S. Pat. No. 8,911,768 titled “Methods For TreatingRetinopathy With Extended Therapeutic Effect” (Allergan, Inc.); U.S.Pat. No. 6,495,164 titled “Preparation of injectable suspensions havingimproved injectability” (Alkermes Controlled Therapeutics, Inc.); WO2014/047439 titled “Biodegradable Microcapsules Containing FillingMaterial” (Akina, Inc.); WO 2010/132664 titled “Compositions And MethodsFor Drug Delivery” (Baxter International Inc. Baxter Healthcare SA);US20120052041 titled “Polymeric nanoparticles with enhanced drug loadingand methods of use thereof” (The Brigham and Women's Hospital, Inc.);US20140178475, US20140248358, and US20140249158 titled “TherapeuticNanoparticles Comprising a Therapeutic Agent and Methods of Making andUsing Same” (BIND Therapeutics, Inc.); U.S. Pat. No. 5,869,103 titled“Polymer microparticles for drug delivery” (Danbiosyst UK Ltd.); U.S.Pat. No. 8,628,801 titled “Pegylated Nanoparticles” (Universidad deNavarra); US2014/0107025 titled “Ocular drug delivery system” (JadeTherapeutics, LLC); U.S. Pat. No. 6,287,588 titled “Agent deliveringsystem comprised of microparticle and biodegradable gel with an improvedreleasing profile and methods of use thereof”, U.S. Pat. No. 6,589,549titled “Bioactive agent delivering system comprised of microparticleswithin a biodegradable to improve release profiles” (Macromed, Inc.);U.S. Pat. Nos. 6,007,845 and 5,578,325 titled “Nanoparticles andmicroparticles of non-linear hydrophilichydrophobic multiblockcopolymers” (Massachusetts Institute of Technology); US20040234611,US20080305172, US20120269894, and US20130122064 titled “Ophthalmic depotformulations for periocular or subconjunctival administration (NovartisAg); U.S. Pat. No. 6,413,539 titled “Block polymer” (Poly-Med, Inc.); US20070071756 titled “Delivery of an agent to ameliorate inflammation”(Peyman); US 20080166411 titled “Injectable Depot Formulations AndMethods For Providing Sustained Release Of Poorly Soluble DrugsComprising Nanoparticles” (Pfizer, Inc.); U.S. Pat. No. 6,706,289 titled“Methods and compositions for enhanced delivery of bioactive molecules”(PR Pharmaceuticals, Inc.); and U.S. Pat. No. 8,663,674 titled“Microparticle containing matrices for drug delivery” (Surmodics).

VI. General Synthesis

The compounds described herein can be prepared by methods known by thoseskilled in the art. In one non-limiting example, the disclosed compoundscan be made using the schemes below.

Compounds of the present invention with stereocenters may be drawnwithout stereochemistry for convenience. One skilled in the art willrecognize that pure or enriched enantiomers and diastereomers can beprepared by methods known in the art. Examples of methods to obtainoptically active materials include at least the following:

-   -   i) physical separation of crystals—a technique whereby        macroscopic crystals of the individual enantiomers are manually        separated. This technique can be used if crystals of the        separate enantiomers exist, i.e., the material is a        conglomerate, and the crystals are visually distinct;    -   ii) simultaneous crystallization—a technique whereby the        individual enantiomers are separately crystallized from a        solution of the racemate, possible only if the enantiomer is a        conglomerate in the solid state;    -   iii) enzymatic resolutions—a technique whereby partial or        complete separation of a racemate by virtue of differing rates        of reaction for the enantiomers with an enzyme;    -   iv) enzymatic asymmetric synthesis—a synthetic technique whereby        at least one step in the synthesis uses an enzymatic reaction to        obtain an enantiomerically pure or enriched synthetic precursor        of the desired enantiomer;    -   v) chemical asymmetric synthesis—a synthetic technique whereby        the desired enantiomer is synthesized from an achiral precursor        under conditions that produce asymmetry (i.e. chirality) in the        product, which may be achieved by chiral catalysts or chiral        auxiliaries;    -   vi) diastereomer separations—a technique whereby a racemic        compound is reaction with an enantiomerically pure reagent (the        chiral auxiliary) that converts the individual enantiomers to        diastereomers. The resulting diastereomers are then separated by        chromatography or crystallization by virtue of their now more        distinct structural differences the chiral auxiliary later        removed to obtain the desired enantiomer;    -   vii) first- and second-order asymmetric transformations—a        technique whereby diastereomers from the racemate quickly        equilibrate to yield a preponderance in solution of the        diastereomer from the desired enantiomer of where preferential        crystallization of the diastereomer from the desired enantiomer        perturbs the equilibrium such that eventually in principle all        the material is converted to the crystalline diastereomer from        the desired enantiomers. The desired enantiomer is then released        from the diastereomer;    -   viii) kinetic resolutions—this technique refers to the        achievement of partial or complete resolution of a racemate (or        of a further resolution of a partially resolved compound) by        virtue of unequal reaction rates of the enantiomers with a        chiral, non-racemic reagent or catalyst under kinetic        conditions;    -   ix) enantiospecific synthesis from non-racemic precursors—a        synthetic technique whereby the desired enantiomer is obtained        from non-chiral starting materials and where the stereochemical        integrity is not or is only minimally compromised over the        course of the synthesis;    -   x) chiral liquid chromatography—a technique whereby the        enantiomers of a racemate are separated in a liquid mobile phase        by virtue of their differing interactions with a stationary        phase (including vial chiral HPLC). The stationary phase can be        made of chiral material or the mobile phase can contain an        additional chiral material to provoke the differing        interactions;    -   xi) chiral gas chromatography—a technique whereby the racemate        is volatilized and enantiomers are separated by virtue of their        differing interactions in the gaseous mobile phase with a column        containing a fixed non-racemic chiral adsorbent phase;    -   xii) extraction with chiral solvents—a technique whereby the        enantiomers are separated by virtue of preferential dissolution        of one enantiomer into a particular chiral solvent;    -   xiii) transport across chiral membranes—a technique whereby a        racemate is place in contact with a thin membrane barrier. The        barrier typically separates two miscible fluids, one containing        the racemate, and a driving force such as concentration or        pressure differential causes preferential transport across the        membrane barrier. Separation occurs as a result of the        non-racemic chiral nature of the membrane that allows only one        enantiomer of the racemate to pass through;    -   xiv) simulated moving bed chromatography is used in one        embodiment. A wide variety of chiral stationary phases are        commercially available.

In some aspects, a compound of Formula I or Formula II can besynthesized according to the route provided in General SynthesisScheme 1. In step 1, compound G1-1 is reacted with butyllithium (oralternatively another organolithium reagent such as, for example,tert-butyllithium, sec-butyllithium, phenyllithium, or methyllithium ora Grignard reagent such as, for example, isopropyl magnesium bromide orethyl magnesium bromide) in an organic solvent (for exampletetrahydrofuran or diethyl ether) at low temperature (typically −78° C.to −40° C.) followed by the addition of G1-2 to provide G1-3. In step 2,compound G1-3 with trifluoroacetic acid (or alternatively another strongoxyacid such as, for example, triflic acid) and triethylsilane (oralternatively another organosilane such as, for example, phenylsilane oran organotin hydride such as, for example, tributyltin hydride) in anorganic solvent (for example 1,2-dichloroethane) with heating (forexample about 60° C. or alternatively with microwave irradiation) toprovide G1-4. In step 3, compound G1-4 is reacted with a base (forexample sodium hydride) in an organic solvent (for exampledimethylformamide or dichloromethane) followed by addition of G1-5 toprovide G1-6.

In some aspects, a compound of Formula I or Formula II can besynthesized according to the route provided in General Synthesis Scheme2. In step 1, compound G2-1 (prepared according to the proceduresoutlined in General Synthesis Scheme 1 for compound G1-3) is reactedwith an oxidant (for example manganese dioxide or other suitable reagentfor the oxidation of alcohols) in organic solvent (for exampleacetonitrile) to provide G2-2. In step 2, G2-2 is reacted with a base(for example sodium hydride) in an organic solvent (for exampledimethylformamide or dichloromethane) followed by addition of G2-3 toprovide G2-4. In step 3, G2-4 is reacted with a suitable carbonylreductant (for example sodium cyanoborohydride) in organic solvent (forexample ethanol or methanol) to provide G2-5.

In some aspects, a compound of Formula I or Formula II can besynthesized according to the route provided in General Synthesis Scheme3. In step 1, Compound G3-1 (prepared according to the proceduresoutlined in General Synthesis Scheme 2 for compound G2-2) is reactedwith DAST (or other suitable nucleophilic fluorination reagent such as,for example, Deoxo-Fluor) in an organic solvent (for exampledichloromethane) to provide G3-2. In step 2, compound G3-2 is reactedwith a base (for example sodium hydride) in an organic solvent (forexample dimethylformamide or dichloromethane) followed by addition ofG3-3 to provide G3-4.

In some aspects, a compound of Formula I or Formula II can besynthesized according to the route provided in General Synthesis Scheme4. In step 1, Compound G4-1 (prepared according to the proceduresoutlined in General Synthesis Scheme 1 for compound G1-3) is reactedwith DAST (or other suitable nucleophilic fluorination reagent such as,for example, Deoxo-Fluor) in an organic solvent (for exampledichloromethane) to provide G4-2. In step 2, compound G4-2 is reactedwith a base (for example sodium hydride) in an organic solvent (forexample dimethylformamide or dichloromethane) followed by addition ofG4-3 to provide G4-4.

In some aspects, a compound of Formula I or Formula II can besynthesized according to the route provided in General Synthesis Scheme5. In step 1, compound G5-1 is reacted with G5-2 in the presence of apalladium catalyst (for example palladium(II) acetate, Pd₂(dba)₃, orother suitable palladium catalyst used in Buchwald-Hartwig couplingconditions), a phosphine ligand (for example BINAP, XantPhos, or othersuitable phosphine ligand used in Buchwald-Hartwig coupling conditions),and a base (for example potassium tert-butoxide, cesium carbonate, orother suitable base used in Buchwald-Hartwig coupling conditions) inorganic solvent (for example toluene, THF, dioxane, or DMF) at elevatedtemperature to provide G5-3. In step 2, compound G5-3 is reacted with abase (for example sodium hydride) in an organic solvent (for exampledimethylformamide or dichloromethane) followed by addition of G5-4 toprovide G5-5.

In some aspects, a compound of Formula I or Formula II can besynthesized according to the route provided in General Synthesis Scheme6. In step 1, compound G6-1 is reacted with a metal hydroxide (forexample sodium hydroxide or potassium hydroxide) in the presence of apalladium catalyst (for example Pd₂(dba)₃) and a phosphine ligand (forexample XantPhos) in an organic solvent (for example dioxane) and waterto provide G6-2. In step 2, G6-2 is protected with an appropriateprotecting group (for example a Boc or Cbz group) using standardconditions to provide compound G6-3. In step 3, G6-3 is reacted withG6-5 in the presence of a copper catalyst (for example copper acetate)and a base (for example pyridine or DMAP) in an organic solvent (forexample 1,2-dichloroethane) at elevated temperature (for example about80° C.) to provide compound G6-6. In step 4, the protecting group PG inG6-6 is removed using standard conditions appropriate for the specificgroup to provide G6-7. In step 5, compound G6-7 is reacted with a base(for example sodium hydride) in an organic solvent (for exampledimethylformamide or dichloromethane) followed by addition of G6-8 toprovide G6-9.

Non-Limiting Examples of the Present Invention

Where chirality is depicted in the synthetic schemes below, thedesignation shows the relative chirality of that stereocenter and not anabsolute designation. For example,

is depicted with a wedged bond to show that the designated chiral centerwas resolved by chiral chromatography. However, the absolute chiralityof that stereocenter may instead be

Then when intermediate 3a is reacted with racemic bromoglutarimide theresulting Compound 280 can be a mixture of diastereomers.

Similarly, where an achiral lactam is reacted in the experimentals belowwith a racemic glutarimide the resulting compound may be a mixture ofenantiomers. For example, when Intermediate 7 is reacted with racemicbromoglutarimide the resulting intermediate 9 may be a mixture ofenantiomers.

The resulting compounds, unless otherwise indicated to have specifiedstereochemistry, may be a mixture of enantiomers. For example,

These mixtures of enantiomers can be separated by the skilled artisanusing techniques known in the art including chiral chromatography,crystallization, transportation across a chiral membrane, or extractionwith a chiral solvent. In fact, these techniques were employed toseparate several of the compounds below. For example, intermediates

were separated by chiral chromatography using a preparative HPLCtechnique. Similarly, enantiomeric mixtures of glutarimides can beresolved by these techniques, including chiral chromatography. Forexample, a mixture of Compounds 67 and Compounds 68 was resolved bychiral chromatography using a preparative HPLC technique. The resultingseparated compounds had an enantiomeric excess of 99%.

Once separated the absolute chirality may be designated by knowntechniques, including various forms of structural determinations ofcrystals. For example, X-ray diffraction may be used on crystals ofcompounds like Compound 67 and Compound 68 to determine if they are (R)or (S).

Mixtures of enantiomers may also be resolved during the syntheticsequence by using techniques known in the art. For example, enzymaticresolution and enzymatic asymmetric synthesis may be used to resolvechiral centers. Additionally, mixtures of enantiomers may be resolved byinstalling a protecting group or using a chiral salt. When chiralprotecting groups or salts are utilized the mixture of enantiomerstemporarily becomes a mixture of diastereomers allowing physicalseparation using known techniques.

Where the compounds of the present invention are a mixture ofdiastereomers they may also be resolved by techniques known in the art.For example, the mixture of diastereomers may be separated bychromatographic techniques, including reverse or normal phase HPLC,chromatography on silica gel, moving bed chromatography, and preparativeTLC. Diastereomeric mixtures may also be separated by crystallization.

Example 1: Synthesis of 3-(2-Oxobenzo[cd]indol-1-yl)piperidine-2,6-dione(Compound 1)

To a stirred solution of 1H-benzo[cd]indol-2-one 1 (100.0 mg, 591.09μmol) in DMF (2 mL) was added sodium hydride (60% dispersion in mineraloil, 24.91 mg, 650.20 μmol, 60% purity) at 0° C., and then the reactionmixture was heated at 60° C. for 30 minutes. 3-bromopiperidine-2,6-dione2 (113.50 mg, 591.09 μmol) was added, and the reaction mixture washeated at 60° C. for 24 hours. A new spot formed along with unreactedstarting material. Additional 3-bromopiperidine-2,6-dione 2 (113.50 mg,591.09 μmol) was added, and the reaction mixture was again heated for 24hours. The reaction mixture was diluted with ethyl acetate, washed withwater and the organic fraction was separated. The reaction mixture wasthen dried over anhydrous sodium sulfate and evaporated under reducedpressure to obtain the crude compound, which was purified by apreparative TLC plate (eluting with 2% MeOH-DCM) to afford3-(2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione (Compound 1) (10 mg,34.35 μmol, 5.81% yield, 96.28% purity) as a pale yellow solid. ¹H NMR(d6-DMSO, 400 MHZ) δ 11.13 (s, 1H), 8.24 (d, J=8.08 Hz, 1H), 8.11 (d,J=6.92 Hz, 1H), 7.84 (t, J=7.56 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.54(t, J=7.76 Hz, 1H), 7.17 (d, J=7.12 Hz, 1H), 5.46 (dd, J=12.76, 5.08 Hz,1H), 3.00-2.91 (m, 1H), 2.82-2.71 (m, 1H), 2.67-2.63 (m, 1H), 2.12-2.09(m, 1H); LC MS: ES+ 281.2.

Example 2: Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 2)

Step 1: Preparation of 6-Bromobenzo[cd]indol-2(1H)-one (2): To thestirred suspension of 1H-benzo[cd]indol-2-one 1 (3.0 g, 17.73 mmol) inCHCl₃ (50.0 mL) was added bromine (2.15 g, 26.60 mmol, 1.44 mL) withcooling drop-wise, and the reaction mixture was stirred at roomtemperature for 48 hours. Sodium thiosulfate solution was poured intothe reaction mixture with cooling, and the yellow solid formed wasfiltered through sintered funnel. The solid obtained was washed withcold water and pentane, and azeotroped with toluene to afford6-bromo-1H-benzo[cd]indol-2-one 2-2 (4 g, 16.12 mmol, 90.93% yield) as ayellow solid. LC MS: ES+ 248.1, 250.0 (bromo pattern).

Step 2: Preparation of tert-Butyl4-(4-(Hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(4): To the stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 2-2 (1.6g, 6.45 mmol) in THF (7 mL) was added butyllithium (2.2 M, 9.38 mL) at−78° C. After the addition was complete, the temperature was allowed toincrease to −40° C., and the reaction mixture was stirred at the sametemperature for 30 minutes. tert-Butyl4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate 3 (1.80 g, 6.45 mmol)in THF (7 mL) was added at −78° C., and the reaction mixture was allowedto warm to room temperature and was stirred for 16 hours. The reactionmixture was quenched with saturated aqueous ammonium chloride solutionand diluted with ethyl acetate. The layers were separated, and theorganic layer was washed with water. The organic layer was then driedover anhydrous sodium sulfate and evaporated under reduced pressure toobtain the crude compound which was purified by flash chromatographyusing 0-5% MeOH-DCM to afford tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate4 (527 mg, 1.17 mmol, 18.22% yield) as a brown solid. 1H NMR (d6-DMSO,400 MHZ) δ 10.70 (s, 1H), 8.34 (d, J=8.28 Hz, 1H), 7.95 (d, J=6.96 Hz,1H), 7.72 (t, J=7.6 Hz, 1H), 7.59-7.52 (m, 2H), 7.28 (s, 1H), 6.93 (d,J=7.2 Hz, 1H), 6.22 (br s, 1H), 5.80 (br s, 1H), 4.27-4.21 (m, 1H),4.00-3.96 (m, 2H), 2.84-2.82 (m, 2H), 1.91-1.87 (m, 2H), 1.72-1.64 (m,2H), 1.39 (s, 9H).

Step 3: Preparation of the 2,2,2-Trifluoroacetic Acid Salt of6-((1-(Piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one(5): To a stirred solution of tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate4 (500.0 mg, 1.11 mmol) in DCE (3 mL) was added triethylsilane (518.51mg, 4.46 mmol, 712.24 μL) and trifluoroacetic acid (1.02 g, 8.92 mmol,687.08 and the reaction was stirred for 30 minutes under microwaveirradiation at 70° C. The solvent in the reaction mixture was evaporatedunder reduced pressure to obtain the crude product which was washed withether and pentane to afford6-[(1-piperidin-1-ium-4-ylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one;2,2,2-trifluoroacetate5 (500.0 mg, 1.12 mmol, 100.47% yield) as a brown gum which was usedwithout further purification. LC MS: ES+ 333.0.

Step 4: Preparation of tert-Butyl4-(4-((2-Oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(6): To a stirred solution of6-[(1-piperidin-1-ium-4-ylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one;2,2,2-trifluoroacetate5 (500.0 mg, 1.12 mmol) in DCM (5 mL) was added triethylamine (340.00mg, 3.36 mmol, 468.32 uL) with cooling followed by the addition ofdi-tert-butyl dicarbonate (366.67 mg, 1.68 mmol, 385.56 uL), and thereaction was continued at room temperature for 16 hours. The reactionmixture was diluted with ethyl acetate, washed with water and brinesolution, and the organic fraction was separated. The organic layer wasthen dried over anhydrous sodium sulfate and evaporated under reducedpressure to obtain the crude which was purified by flash chromatography(using 0-5% MeOH-DCM) to afford tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate6 (300.0 mg, 693.62 μmol, 61.93% yield) as a yellow sticky solid. LC MS:ES+ 433.0.

Step 5: Preparation of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 2): To a stirred solution of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate6 (300.0 mg, 693.62 μmol) in DMF (1 mL) was added sodium hydride (60%dispersion in mineral oil, 53.15 mg, 1.39 mmol, 60% purity) withcooling, and the reaction mixture was heated at 60° C. for 30 minutes.3-bromopiperidine-2,6-dione 7 (133.18 mg, 693.62 μmol) was then added,the reaction was heated at 60° C. for 4 hours followed by a furtheraddition of 3-bromopiperidine-2,6-dione (133.18 mg, 693.62 μmol), andthe reaction was further stirred for 16 hours at 60° C. The reactionmixture was diluted with ethyl acetate and washed with water, and theorganic fraction was separated. The reaction mixture was then dried overanhydrous sodium sulfate and evaporated under reduced pressure to obtainthe crude which was first purified by column chromatography followed bya preparative TLC plate (eluting with 60% ethyl acetate-hexane) toafford tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate(Compound 2) (20.0 mg, 33.11 μmol, 4.77% yield, 90% purity) as a paleyellow solid. ¹H NMR (d6-DMSO, 400 MHZ) δ 11.11 (s, 1H), 8.37 (d, J=8.24Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.83 (t, J=7.58 Hz, 1H), 7.59 (s, 1H),7.35 (d, J=7.36 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43(dd, J=12.76, 5.0 Hz, 1H), 4.24-4.23 (m, 1H), 4.17 (s, 2H), 4.00-3.96(m, 2H), 2.96-2.66 (m, 5H), 2.09-2.06 (m, 1H), 1.91-1.88 (m, 2H),1.72-1.66 (m, 2H), 1.39 (m, 9H); LC MS: ES+ 544.3.

Example 3. Synthesis of3-(6-((1-(1-(Cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 3)

Step 1: Preparation of3-(2-Oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dioneHydrochloride (2): To the stirred solution of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate1 (100.0 mg, 183.95 μmol) in dioxane (1 mL) was added hydrochloric acidin dioxane (183.95 μmol, 8 mL), and the reaction was stirred at roomtemperature for 2 hours. TLC analysis showed complete consumption of thestarting material. The solvent in the reaction mixture was evaporatedunder reduced pressure, and the residue was washed with ether andpentane to afford3-[6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione2 (88.0 mg, 183.35 μmol, 99.67% yield) as a yellow solid. LC MS: ES+444.1.

Step 2: Preparation of3-(6-((1-(1-(Cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 3): To a stirred solution of3-[6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione2 (88.0 mg, 183.35 μmol) in DMF (3.0 mL) were added cubane-1-carboxylicacid (27.16 mg, 183.35, followed by HATU (104.57 mg, 275.02 μmol) andN,N-diisopropylethylamine (71.09 mg, 550.05 μmol, 95.81 uL) at 0° C. Thereaction mixture was then stirred at room temperature for 16 hours. Itwas diluted with ethyl acetate and water, and the layers were separated.The organic layer was washed with saturated aqueous NaHCO₃ solution,water, and brine, dried over sodium sulfate, and concentrated. The crudematerial was purified by Prepatory TLC (eluting with 3% MeOH/DCM) to get3-[6-[[1-[1-(cubane-1-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 3) (55.0 mg, 94.77 μmol, 51.69% yield, 98.84% purity) as ayellow solid. ¹H NMR (d6-DMSO, 400 MHZ) δ 11.09 (s, 1H), 8.36 (d, J=8.16Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.83 (t, J=7.62 Hz, 1H), 7.60 (s, 1H),7.35 (d, J=7.32 Hz, 1H), 7.31 (s, 1H), 7.06 (d, J=7.24 Hz, 1H), 5.42(dd, J=12.48, 5.24 Hz, 1H), 4.33-4.31 (m, 2H), 4.18 (br s, 5H), 3.97 (brs, 4H), 3.38-3.34 (m, 1H), 3.20-3.13 (m, 1H), 2.97-2.90 (m, 1H),2.79-2.62 (m, 3H), 2.10-2.07 (m, 1H), 2.01-1.92 (m, 2H), 1.83-1.79 (m,1H), 1.67-1.64 (m, 1H); LC MS: ES+ 574.5.

Example 4: Synthesis of3-(6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 4)

Step 1: Preparation of6-((1-(Piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-oneHydrochloride (2): To a stirred solution of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate1 (100.0 mg, 183.95 μmol) in dioxane (1 mL) was added hydrochloric acidin dioxane (183.95 μmol, 8 mL), and the reaction was stirred at roomtemperature for 2 hours. The solvent in the reaction mixture wasevaporated under reduced pressure, and the residue was washed with etherand pentane to afford3-[6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione2 (88.0 mg, 183.35 μmol, 99.67% yield) as a yellow solid. LC MS: ES+444.1.

Step 2: Preparation of6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one:To a stirred solution of6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one2 (98.0 mg, 265.68 μmol) and 1-methylcyclobutanecarboxylic acid 3 (30.33mg, 265.68 μmol) in DMF (2.0 mL) at 0° C. was added HATU (151.53 mg,398.53 μmol) and N,N-diisopropylethylamine (171.69 mg, 1.33 mmol, 231.38uL), and the reaction mixture was stirred at room temperature for 16hours. The reaction mixture was then extracted with ethyl acetate, andthe combined organic layer was washed with water and saturated sodiumbicarbonate solution, and dried over sodium sulfate. The organic layerwas then concentrated under reduced pressure to afford the crudeproduct. The crude residue was purified by CombiFlash chromatography(eluting 1%-1.5% MeOH in DCM) to afford6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one4 (66 mg, 154.02 μmol, 57.97% yield) as a pale yellow solid. LC MS: ES+429.3

Step 3: Preparation of3-(6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 4): To a stirred solution of6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one4 (66.0 mg, 154.02 μmol) in DMF (1 mL) was added sodium hydride (60%dispersion in mineral oil, 11.80 mg, 308.03 μmol) under cooling, and thereaction mixture was heated at 60° C. for 30 minutes.3-bromopiperidine-2,6-dione 5 (29.57 mg, 154.02 μmol) was then added,and the reaction was heated at 60° C. for 4 hours followed by thefurther addition of 3-bromopiperidine-2,6-dione (29.57 mg, 154.02 mol),and the reaction was further continued for 16 hours at 60° C. Thereaction mixture was diluted with ethyl acetate and washed with water,and the organic fraction was separated. The organic layer was then driedover anhydrous sodium sulfate and evaporated under reduced pressure toobtain the crude product which was first purified by columnchromatography followed by preparative TLC (developing the plate in 60%ethyl acetate-DCM) to afford3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 4) (15.0 mg, 27.21 mol, 17.66% yield, 97.87% purity) as paleyellow solid. ¹H NMR (d6-DMSO, 400 MHZ) δ 11.11 (s, 1H), 8.37 (d, J=8.44Hz, 1H), 8.08 (d, J=6.44 Hz, 1H), 7.85-7.83 (m, 1H), 7.60 (s, 1H), 7.35(d, J=7.12 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=6.84 Hz, 1H), 5.46-5.42 (m,1H), 4.39-4.37 (m, 1H), 4.31-4.29 (m, 1H), 4.18 (s, 2H), 3.60-3.58 (m,1H), 3.04-2.91 (m, 3H), 2.77-2.62 (m, 2H), 2.41-2.32 (m, 3H), 2.09-2.07(m, 1H), 1.92-1.90 (m, 3H), 1.78-1.76 (m, 3H), 1.64-1.61 (m, 2H), 1.33(s, 3H); LC MS: ES+ 540.4.

Example 5. Synthesis ofN-(tert-Butyl)-4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-N-methylpiperidine-1-carboxamide(Compound 5)

To an equi-molar mixture of HCl salt 1 and tert-butyl(methyl)carbamicchloride in DMF (6 mL/mmol) is added DIPEA (4.0 equiv) at 0° C. Theresulting solution is stirred at ambient temperature for 16 hours. Thereaction mixture is then diluted with ethyl acetate and washed withaqueous NaHCO₃ solution, water (×3) and brine. The organic layer is thendried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude mass is then purified by CombiFlash ISCO column, eluting with 2%methanol in DCM to affordN-(tert-Butyl)-4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-N-methylpiperidine-1-carboxamide(Compound 5).

Example 6. Synthesis of tert-Butyl4-(4-(1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 6) and tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)(hydroxy)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 7)

Step 1: Synthesis of tert-Butyl4-(4-(2-Oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(2): To a stirred solution of tert-butyl4-(4-(hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate1 in acetonitrile is added manganese(IV) oxide (10 equiv.) and thereaction mixture is stirred at room temperature for 16 hr. TLC and LCMSshow product formation. The reaction mixture is filtered through acelite pad, and the filtrate is concentrated under reduced pressure toget a crude mass which is purified by combiflash chromatography using1.5% MeOH-DCM as eluent to afford desired product tert-butyl4-(4-(2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate2.

Step 2: Synthesis of tert-Butyl4-(4-(1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 6): To the stirred solution of compound 2 in THF is addedsodium hydride (60% dispersion in mineral oil, 1 equiv.) and thereaction mixture is refluxed at 60° C. for 30 minutes. A solution of(3-bromopiperidine-2,6-dione) (0.5 equiv.) in THF is also heated at 60°C. After 30 minutes the first suspension is added to the secondsolution, and the heating is continued for 3 hours. The reaction mixtureis diluted with ethyl acetate and washed with water and brine solution.The organic fraction is then dried over anhydrous sodium sulfate andevaporated under reduced pressure to obtain the crude compound. Thecrude compound is then purified by flash chromatography to obtainCompound 6.

Step 3: Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)(hydroxy)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 7): A stirred solution of Compound 6 in ethanol is cooled to0° C., and sodium borotriacetoxyhydride (1.2 equiv.) is added to thereaction mixture. The reaction mixture is stirred at room temperaturefor 16 hours. It is quenched with water and extracted with ethylacetate. The combined organic phase is dried over sodium sulfate,concentrated and purified by column chromatography using (silica,gradient, 0%-2% Methanol in DCM) to provide Compound 7.

Example 7. Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)difluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 8)

Step 1: Synthesis of tert-Butyl4-(4-(Difluoro(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(2): To a stirred solution of 1 in DCM is added DAST (3 equiv.) at −30°C., and the reaction mixture is stirred at the same temperature for 30minutes and then slowly brought up to room temperature. LC-MS shows thedesired product. It is quenched with water and extracted with ethylacetate. The combined organic phase is dried over sodium sulfate,concentrated and purified by column chromatography using (silica,gradient, 0%-2% Methanol in DCM) to provide 2.

Step 2: Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)difluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 8): To a stirred solution of compound 2 in THF is added sodiumhydride (60% dispersion in mineral oil, 1 equiv.), and the reactionmixture was refluxed at 60° C. for 30 minutes. A solution of3-bromopiperidine-2,6-dione 3 (0.5 equiv.) in THF is also heated at 60°C. After 30 minutes the first suspension is added to the second solutionwith heating, and the heating is continued for 3 hours. The reactionmixture is diluted with ethyl acetate and washed with water and brinesolution. The organic phase is then dried over anhydrous sodium sulfateand evaporated under reduced pressure to obtain the crude compound. Thecrude compound is then purified by flash chromatography to Compound 8.

Example 8: Synthesis of3-(6-(4-(Morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 9)

Step 1-3: 4-(Morpholinomethyl)benzaldehyde was prepared in Steps 1-3according to the literature procedure provided in WO 2015/086636.

Step 4: Synthesis of6-(Hydroxy(4-(morpholinomethyl)phenyl)methyl)benzo[cd]indol-2(1H)-one(7): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 6 (1equiv.) in THF is added butyllithium (2.2 equiv.) at −78° C. After theaddition is complete the temperature is allowed to increase to −40° C.,and the reaction mixture is stirred at the same temperature for 30minutes. 5 (1 eq) in THF (7 mL) is added at −78° C., and then thereaction mixture is allowed to warm to room temperature and is stirredfor 16 hours. The reaction mixture is quenched with saturated aqueousammonium chloride solution and diluted with ethyl acetate. The layersare separated, and the organic phase was washed with water. The organicphase is then dried over anhydrous sodium sulfate and evaporated underreduced pressure to obtain the crude compound which is purified by flashchromatography using 0-5% MeOH-DCM to afford the desired product 7.

Step 5: Synthesis of6-(4-(Morpholinomethyl)benzyl)benzo[cd]indol-2(1H)-one (8): To a stirredsolution of 7 in DCE is added triethylsilane (3 equiv.) andtrifluoroacetic acid (10 equiv.), and the reaction is stirred for 30minutes under microwave irradiation at 70° C. The solvent in thereaction mixture is evaporated under reduced pressure to obtain thecrude product which is washed with ether and pentane to afford 8 as abrown gum that is used without further purification.

Step 6: Synthesis of3-(6-(4-(Morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 9): To the stirred solution of 8 in THF is added sodiumhydride (60% dispersion in mineral oil, 1 equiv.), and the reactionmixture is refluxed at 60° C. for 30 minutes. A solution of3-bromopiperidine-2,6-dione 9 (0.5 equiv.) in THF is also heated at 60°C. After 30 minutes the first suspension is added to the second solutionwith heating, and the heating is continued for 3 hours. The reactionmixture is diluted with ethyl acetate and washed with water and brinesolution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound is then purified by flash chromatography toobtain Compound 9.

Example 9. Synthesis of3-(6-Amino-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound10)

Step 1: Synthesis of 6-Nitrobenzo[cd]indol-2(1H)-one (2): To a stirredsolution of 1 in acetic acid is added nitric acid at 0° C., and theresulting reaction mixture is stirred at room temperature for 1 hr.Progress of the reaction was monitored by TLC. After completion, thereaction mixture is added to ice-water and extracted with ethyl acetate.The combined organic layer is washed with brine solution and dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toafford the desired product 2 which is further purified by columnchromatography or recrystallization.

Step 2: Synthesis of3-(6-Nitro-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (4): To thestirred solution of compound 2 in THF is added sodium hydride (60%dispersion in mineral oil, 1 equiv.), and the reaction mixture isrefluxed at 60° C. for 30 minutes. A solution of3-bromopiperidine-2,6-dione 3 (0.5 equiv.) in THF was also heated at 60°C. After 30 minutes the first suspension was added to the secondsolution with heating, and the heating was continued for 3 hours. Thereaction mixture was diluted with ethyl acetate and washed with waterand brine solution. The organic fraction was then dried over anhydroussodium sulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound was then purified by flash chromatographyto obtain 4.

Step 3: Synthesis of3-(6-Amino-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound10): A stirred solution of 4 in ethanol was degassed with argon for 10minutes. 10% Pd/C (30 Wt %) was added to the reaction mixture, and itwas subjected to hydrogenation under a hydrogen balloon for 16 hours. Itwas filtered through celite and concentrated under reduced pressure toobtain Compound 10 as solid.

Example 10. Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 11) and3-(6-((1-(1-((2r,3r,5r,6r,7r,8r)-Cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 12)

Step 1: Synthesis of tert-Butyl4-(4-((2-Oxo-1,2-dihydrobenzo[cd]indol-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(3): To a stirred solution of tert-butyl4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (20 mg, 75.09 μmol) and6-bromo-1H-benzo[cd]indol-2-one (18.63 mg, 75.09 μmol) intoluene (5 mL)in a sealed tube was added potassium tert butoxide (25.28 mg, 225.28μmol), and the reaction mixture was degassed for 5 min under argonatmosphere. Pd₂(dba)₃ (6.88 mg, 7.51 μmol) and BINAP (4.68 mg, 7.51μmol) were added, and the reaction mixture was again purged for 2 minunder argon atmosphere. The reaction mixture was heated to 90° C. for 16hr. After consumption of SM reaction, the mixture was filtered through acelite bed and concentrated in vacuo. Purification by CombiFlash columnchromatography (eluted by 15% ethyl acetate in n-hexane) providedtert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate3 as a yellow liquid. LCMS (ES+)=249.9 [M+H]+.

Step 2: Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 11): To a stirred solution of compound 3 in THF is addedsodium hydride (60% dispersion in mineral oil, 1 equiv.), and thereaction mixture is refluxed at 60° C. for 30 minutes. A solution of3-bromopiperidine-2,6-dione 4 (0.5 equiv.) in THF is also heated at 60°C. After 30 minutes the first suspension is added to the second solutionwith heating, and the heating is continued for 3 hours. The reactionmixture is diluted with ethyl acetate and washed with water and brinesolution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound is then purified by flash chromatography toobtain Compound 11.

Step 3: Synthesis of3-(2-Oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(5): To a stirred solution of Compound 11 in 1,4 dioxane is added HCl indioxane (4 M). The reaction mixture is stirred at 25° C. for 16 hr.After complete consumption of the starting material, the reaction isconcentrated under reduced pressure. The resulting solid is washed with10-20% ethyl acetate in n-hexane and dried to give the title compound 5.

Step 4: Synthesis of3-(6-((1-(1-((2r,3r,5r,6r,7r,8r)-Cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 12): To a stirred solution of 5 and cubane-1-carboxylic acid(1 equiv.) in DMF (2 mL) is added HATU (1.5 equiv.) and DIPEA (3equiv.), and the reaction mixture is stirred at 25° C. for 16 hr.Completion of the reaction is determined by LC-MS. The reaction mixtureis diluted with ethyl acetate and washed with water. The organic layeris separated, dried over sodium sulfate, and concentrated under reducedpressure to give the crude. This crude is purified by preparatory TLC(using 100% ethyl acetate) to give the Compound 12 as a solid.

Example 11. Synthesis of3-(6-(4-(Morpholinomethyl)phenoxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 13)

Step 1: Synthesis of 6-Hydroxybenzo[cd]indol-2(1H)-one (2): To a stirredsolution of 1 in dioxane (8 mL) and water (2 mL), potassium hydroxide (2equiv) is added, and the resulting solution is degassed with N₂ for 15minutes followed by the addition of(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (5%) and tert-butylXphos (15%). The reaction mixture is heated at 100° C. in a sealed tubefor 12 hr. After formation of desired pdt as evidence from LC-MS, thereaction mixture is filtered through celite bed and washed with ethylacetate. The combined organic layer is separated and evaporated. Thecrude residue is purified by column chromatography to afford 2 as asolid.

Step 2: Synthesis of tert-Butyl6-Hydroxy-2-oxobenzo[cd]indole-1(2H)-carboxylate (3): To a stirredsolution of 2 in methanol (5 mL) and triethylamine (2 equiv.) is slowlyadded di-tert-butyl dicarbonate (1.5 eq). After completion of thereaction as confirmed by TLC and LC-MS, the solvent is removed. Thecrude is extracted with ethyl acetate and water. The organic layer isdried over with Na₂SO₄. The solvent is removed under vacuum to get thedesired product 3.

Step 3: Synthesis of tert-Butyl6-(4-(Morpholinomethyl)phenoxy)-2-oxobenzo[cd]indole-1(2H)-carboxylate(5): To a stirred solution of 3 and 4 in DCE is added pyridine (2equiv.). The reaction mixture is degassed with oxygen followed by theaddition of copper acetate (0.1 equiv.) and DMAP (0.1 equiv). Thereaction mixture is heated at 80° C. for 24 hr. After completion of thereaction, the solvent is removed, and the crude is extracted with ethylacetate and water. The organic layer is dried over with Na₂SO₄, and thesolvent is removed under vacuum to get desired product 5.

Step 4: Synthesis of6-(4-(Morpholinomethyl)phenoxy)benzo[cd]indol-2(1H)-one (6): To astirred solution of 5 (1 equiv.) in DCM is added TFA (10.0 equiv.). Theresulting solution is stirred at RT for 4 hr. The reaction is monitoredby LCMS and TLC. After completion, the reaction is concentrated underreduced pressure to get crude compound 6 that is directly used in thenext step without any other purification.

Step 5: Synthesis of3-(6-(4-(Morpholinomethyl)phenoxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 13): To the stirred solution of compound 6 in THF is addedsodium hydride (60% dispersion in mineral oil, 1 equiv.), and thereaction mixture is refluxed at 60° C. for 30 minutes. A solution of3-bromopiperidine-2,6-dione 7 (0.5 equiv.) in THF is also heated at 60°C. After 30 minutes the first suspension is added to the second solutionwith heating, and the heating is continued for 3 hours. The reactionmixture is diluted with ethyl acetate and washed with water and brinesolution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound is then purified by flash chromatography toobtain Compound 13.

Example 12. Synthesis of3-(6-((1-(1-((1-Methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 14)

Step 1: Synthesis of6-((1-(1-((1-Methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one(3): To a stirred solution of 1 and 1-methylcyclobutane-1-carbaldehyde 2(1 equiv.) in dry dichloroethane (3 mL) was added sodiumcyanoborohydride (2 equiv.) at 0° C., and the reaction mixture wasstirred at 0° C. for 2 h. The reaction is warmed to rt over the periodof 1 h and stirred at rt for 12 h. The completion of the reaction isconfirmed by TLC. The reaction mixture is quenched with water (25 mL)and extracted with DCM (2×25 mL). The combine organic layer is furtherwashed with brine (1×25 mL), dried over anhydrous Na₂SO₄, andconcentrated to get the crude product 3.

Step 2: Synthesis of3-(6-((1-(1-((1-Methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 14): To the stirred solution of compound 3 in THF is addedsodium hydride (60% dispersion in mineral oil, 1 equiv.), and thereaction mixture is refluxed at 60° C. for 30 minutes. A solution of3-bromopiperidine-2,6-dione 4 (0.5 equiv.) in THF is also heated at 60°C. After 30 minutes the first suspension is added to the second solutionwith heating, and the heating is continued for 3 hours. The reactionmixture is diluted with ethyl acetate and washed with water and brinesolution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound is then purified by flash chromatography toobtain Compound 14.

Example 13: Synthesis of3-(6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 15)

Step 1: Synthesis of tert-Butyl 4-Azidopiperidine-1-carboxylate (2): Toa DMF solution of 1 is added sodium azide (3 equiv.), and the reactionmixture is heated under reflux at 70° C. for 2 hours. The reaction ismonitored by TLC to observe consumption of starting material. Thereaction is quenched with water and extracted with ethyl acetate. Theethyl acetate layer is washed with brine, dried over anhydrous Na₂SO₄and evaporated to get crude compound. The crude compound is purified bysilica gel column chromatography to get pure compound 2 as a whitesolid.

Step 2: Synthesis of tert-Butyl4-(4-(Diethoxymethyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate 3:To a stirred solution of tert-butyl 4-azidopiperidine-1-carboxylate 2and 3,3-diethoxyprop-1-yne in Water and DMSO (1:4) is added coppersulfate (5%) at 25° C. The reaction is stirred for 5 min followed byaddition of sodium ascorbate (15%). The reaction mixture is then stirredfor 2 h at 25° C. The reaction is diluted with cold water and extractedwith ethyl acetate (2×). The combined organic layers are dried overanhydrous sodium sulfate and concentrated under reduced pressure toyield crude product. The crude product is purified by silica gel columnchromatography to provide 3.

Step 3: Synthesis of 1-(Piperidin-4-yl)-1H-1,2,3-triazole-4-carbaldehyde4: To a stirred solution of 3 in 1,4 dioxane is added HCl in dioxane (4M). The reaction mixture is stirred at 25° C. for 16 hr. After completeconsumption of SM, the reaction is concentrated under reduced pressure,washed with 10-20% ethyl acetate in n-hexane, and dried to give thetitle compound 4 as a solid.

Step 4: Synthesis of1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazole-4-carbaldehyde(6): To a stirred solution of 4 and 1-methylcyclobutane-1-carboxylicacid 5 (1 equiv.) in DMF (2 mL) is added HATU (1.5 equiv.) and DIPEA (3equiv.), and the reaction mixture is stirred at 25° C. for 16 hr.Completion of the reaction is confirmed by LC-MS, and the reactionmixture is diluted with ethyl acetate and washed with water. The organiclayer is separated, dried over sodium sulfate, and concentrated underreduced pressure to give the crude. The crude is purified by silica gelcolumn chromatography to give the title compound 6 as solid.

Step 5: Synthesis of6-(Hydroxy(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)benzo[cd]indol-2(1H)-one(8): To the stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 7 (1equiv.) in THF is added butyllithium (2.2 equiv.) at −78° C., and thetemperature is allowed to increase to −40° C. The reaction mixture isstirred at the same temperature for 30 minutes followed by the additionof 6 (1 equiv.) in THF at −78° C., and then the reaction mixture isallowed to warm to room temperature and stirred for 16 hours. Thereaction mixture is quenched with saturated aqueous ammonium chloridesolution and diluted with ethyl acetate. The layers are separated, andthe organic phase is washed with water. The organic layer is dried overanhydrous sodium sulfate and evaporated under reduced pressure to obtainthe crude compound which is purified by flash chromatography using 0-5%MeOH-DCM to afford desired product 8.

Step 6: Synthesis of6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)benzo[cd]indol-2(1H)-one(9): To a stirred solution of 8 in DCE is added triethylsilane (2equiv.) and trifluoroacetic acid (5 equiv.), and the reaction is stirredfor 30 minutes under microwave irradiation at 70° C. The solvent isevaporated under reduced pressure to obtain the crude which is washedwith ether and pentane to afford 9 as a brown gum in the form of crude.

Step 7: Synthesis of3-(6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 15): To the stirred solution of compound 9 in THF is addedsodium hydride (60% dispersion in mineral oil, 1 equiv.), and thereaction mixture is refluxed at 60° C. for 30 minutes. A solution of3-bromopiperidine-2,6-dione 10 (0.5 equiv.) in THF is also heated at 60°C. After 30 minutes the first suspension is added to the second solutionwith heating, and the heating is continued for 3 hours. The reactionmixture is diluted with ethyl acetate and washed with water and brinesolution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound is then purified by flash chromatography toobtain Compound 15.

Example 14. Synthesis of3-(6-((3-Chloro-1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 16)

Step 1: Synthesis of tert-Butyl4-(5-Amino-4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(3a) and tert-butyl4-(3-amino-4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(3b): To a stirred solution of ethyl 5-amino-1H-pyrazole-4-carboxylate 1(10.0 g, 64.45 mmol) in DMF (100 mL) was added tert-butyl4-methylsulfonyloxypiperidine-1-carboxylate 2 (25.21 g, 90.23 mmol) andCesium carbonate (42.00 g, 128.90 mmol), and the reaction mixture wasstirred at 80° C. for 16 hours. TLC showed the formation of the twoisomeric new spots and consumption of both starting materials. Thereaction mixture was then cooled to room temperature, diluted with ethylacetate, and washed with water. The organic layer was dried over sodiumsulfate and concentrated under reduced pressure. The crude was thenpurified by column chromatography eluting 10-12% ethyl acetate indichloromethane to afford 3a (4.5 g, 13.30 mmol, 20.63% yield) as awhite solid and eluting 15-20% ethyl acetate in dichloromethane toafford 3b (4.8 g, 14.18 mmol, 22.01% yield) as a white solid.

Step 2: Synthesis of tert-Butyl4-(3-Chloro-4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(4): To a stirred solution of tert-butyl4-(3-amino-4-ethoxycarbonyl-pyrazol-1-yl)piperidine-1-carboxylate (2.1g, 6.21 mmol) in acetonitrile (10.0 mL) at 0° C. was added tert-Butylnitrite (tech. 90%, 959.89 mg, 9.31 mmol, 1.11 mL) followed by CuCl(921.53 mg, 9.31 mmol), and the reaction mixture was stirred at roomtemperature for 1 hour. The reaction was heated at 65° C. for 2 hours.TLC showed a new non-polar spot and starting material was consumed. Thereaction mixture was then cooled to room temperature, diluted with ethylacetate, and washed with water. The organic layer was washed withsaturated sodium bicarbonate solution and brine solution, dried oversodium sulfate, and concentrated under reduced pressure to afford thecrude product. The crude was then purified by column chromatographyeluting 1-1.5% MeOH-DCM to afford tert-butyl 4-(3-chloro-4-ethoxycarbonyl-pyrazol-1-yl)piperidine-1-carboxylate 4 (1 g, 2.79 mmol, 45.03%yield) as a gummy green liquid.

Step 3: Synthesis of tert-Butyl4-(3-Chloro-4-(hydroxymethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(5): To a stirred solution of 4 in THF at 0° C. under inert atmosphereis added DIBAL-H (4 equiv., 25% intoluene) drop-wise. After completionof addition, the mixture is stirred at same temperature for 1 h. UponTLC showing starting material consumption, the mixture is quenched withwater and diluted with EtOAc. The solid precipitate is filtered througha celite pad, and the filtrate is concentrated to dryness to afford 5 ascrude.

Step 4: Synthesis of tert-Butyl4-(3-Chloro-4-formyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (6): To astirred solution of 5 in DCM is added manganese dioxide (10 equiv.), andthe reaction was stirred at room temperature overnight. Upon completionof the reaction, the reaction mixture is filtered, and the filtrate isevaporated under reduced pressure. The crude material is then purifiedby column chromatography to afford 6.

Step 5: Synthesis of tert-Butyl4-(3-Chloro-4-(hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(8): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 7 (1equiv.) in THF is added butyllithium (2.2 equiv.) at −78° C., and afterthe addition is complete the temperature is allowed to increase to −40°C. and stirred for 30 minutes. 6 (1 equiv.) in THF is added at −78° C.,and then the reaction mixture is allowed to warm to room temperature andis stirred for 16 hours. The reaction mixture is quenched with saturatedaqueous ammonium chloride solution and diluted with ethyl acetate. Thelayers are separated, and the organic layer is washed with water. Theorganic phase is dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to obtain the crude compound, which is purifiedby flash chromatography using 0-5% MeOH-DCM to afford desired product 8.

Step 6: Synthesis of tert-Butyl4-(3-Chloro-4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(9): To a stirred solution of 8 in DCE is added triethylsilane (2equiv.) and trifluoroacetic acid (5 equiv.), and the reaction is stirredfor 30 minutes under microwave irradiation at 70° C. The solvent isevaporated under reduced pressure to obtain the crude which is washedwith ether and pentane to afford 9 as brown gum in the form of crude.

Step 7: Synthesis of tert-Butyl4-(3-Chloro-4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(11): To the stirred solution of compound 9 in THF is added sodiumhydride (60% dispersion in mineral oil, 1 equiv.), and the reactionmixture is refluxed at 60° C. for 30 minutes. A solution of3-bromopiperidine-2,6-dione 10 (0.5 equiv.) in THF is also heated at 60°C. After 30 minutes the first suspension is added to the second solutionwith heating, and the heating is continued for 3 hours. The reactionmixture is diluted with ethyl acetate and washed with water and brinesolution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound is then purified by flash chromatography toobtain 11.

Step 8: Synthesis of3-(6-((3-Chloro-1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(12): To a stirred solution of 11 in dioxane is added hydrochloric acidin dioxane (10 equiv.), and the reaction is stirred at room temperaturefor 2 hours. TLC is checked for complete consumption of the startingmaterial. The solvent in the reaction mixture is evaporated underreduced pressure, and the crude is washed with ether and pentane toafford 12 as a solid.

Step 9: Synthesis of3-(6-((3-Chloro-1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 16): To a stirred solution of 12 and1-methylcyclobutane-1-carboxylic acid 13 (1 equiv) in DMF (2 mL) isadded HATU (1.5 eq) and DIPEA (3 eq), and the reaction mixture isstirred at 25° C. for 16 hr. Upon completion of the reaction asdetermined by LC-MS, the reaction mixture is diluted with ethyl acetateand washed with water. The organic layer is separated, dried over sodiumsulfate, and concentrated under reduced pressure to give the crude. Thiscrude is purified by silica gel column chromatography to give Compound16 as a solid.

Example 15. Synthesis of3-(6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 17)

Step 1: Synthesis of tert-Butyl4-(3-Formyl-1H-pyrrolo[2,3-c]pyridin-1-yl)piperidine-1-carboxylate (3):To a solution of 1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde 1 (250 mg,1.71 mmol) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate 2(1 equiv.) in DMF (5 mL) was added cesium carbonate (1.11 g, 3.42 mmol),and the reaction was heated to 80° C. for 16 hr. LC-MS showed formationof product with majority SM. Another equiv of tert-butyl4-methylsulfonyloxypiperidine-1-carboxylate was added, and the reactionwas heated at 90° C. for another 16 h. LC-MS showed formation ofmajority product. The reaction was cooled to rt, diluted with water andextracted with EtOAc successively. The combined organic phase was washedwith water and brine and dried over sodium sulfate. The crude waspurified by CombiFlash eluting with 100% EtOAc to get tert-butyl4-(3-formylpyrrolo[2,3-c]pyridin-1-yl)piperidine-1-carboxylate 3 (300mg, 910.77 μmol, 53.24% yield) as pure product. LCMS (ES+)=330.2 [M+H]⁺.

Step 2: Synthesis of1-(Piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (4): To asolution of tert-butyl4-(3-formylpyrrolo[2,3-c]pyridin-1-yl)piperidine-1-carboxylate 3 (200mg, 607.18 μmol) in dioxane (15 mL) was added dioxane-HCl (4 M, 455.38μL), and the reaction was stirred at 25° C. for 16 h. LC-MS showedformation of product. The reaction was evaporated to dryness to provide1-(4-piperidyl)pyrrolo[2,3-c]pyridine-3-carbaldehyde hydrochloride 4(155 mg, 583.28 μmol, 96.06% yield) as a white solid.

Step 3: Synthesis of1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde(6): To a solution of1-(4-piperidyl)pyrrolo[2,3-c]pyridine-3-carbaldehyde hydrochloride 4(780 mg, 2.94 mmol) and 1-methylcyclobutanecarboxylic acid 5 (335.03 mg,2.94 mmol) in DMF (50 mL) was added DIPEA (1.14 g, 8.81 mmol, 1.53 mL),and the reaction was stirred for a few minutes at 25° C. HATU (1.34 g,3.52 mmol) was added to the reaction mixture, and stirring was continuedfor 16 hr. LC-MS showed formation of product. Water was added, and thereaction mixture was extracted with EtOAc. The organic phase was washedwith water, brine and dried over Na₂SO₄. The crude was evaporated todryness and purified by prep TLC eluting with 3% MeOH in DCM to afford1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrrolo[2,3-c]pyridine-3-carbaldehyde6 (820 mg, 2.52 mmol, 85.85% yield) as a yellow solid. LCMS (ES+)=326.2[M+H]+.

Step 4: Synthesis of6-(Hydroxy(l-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)benzo[cd]indol-2(1H)-one(8): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 7 (1equiv.) in THF is added butyllithium (2.2 equiv.) at −78° C. Uponaddition, the temperature is allowed to increase to −40° C. and thereaction mixture is stirred at the same temperature for 30 minutes. 6 (1equiv.) in THF is added at −78° C., and the reaction mixture is allowedto warm to room temperature and is stirred for 16 hours. The reactionmixture is quenched with saturated aqueous ammonium chloride solutionand diluted with ethyl acetate. The layers are separated, and theorganic phase is washed with water. The organic layer is dried overanhydrous sodium sulfate and evaporated under reduced pressure to obtainthe crude compound which is purified by flash chromatography using 0-5%MeOH-DCM to afford desired product 8.

Step 5: Synthesis of6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)benzo[cd]indol-2(1H)-one(9): To a stirred solution of 8 in DCE is added triethylsilane (2equiv.) and trifluoroacetic acid (5 equiv.), and the reaction is stirredfor 30 minutes under microwave irradiation at 70° C. The solvent isevaporated under reduced pressure to obtain the crude which is washedwith ether and pentane to afford 9 as brown gum in the form of crude.

Step 6: Synthesis of3-(6-((1-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 17): To a stirred solution of compound 9 in THF is addedsodium hydride (60% dispersion in mineral oil, 1 equiv.), and thereaction mixture is refluxed at 60° C. for 30 minutes. A solution of3-bromopiperidine-2,6-dione 10 (0.5 equiv.) in THF is also heated at 60°C. After 30 minutes the first suspension is added to the second solutionwith heating, and the heating is continued for 3 hours. The reactionmixture is diluted with ethyl acetate and washed with water and brinesolution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound is then purified by flash chromatography toobtain Compound 17.

Example 16. Synthesis of3-(6-((1-(1-(Cubane-1-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 18)

Step 1: Preparation of tert-Butyl4-(4-(Hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carboxylate(3): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 1 (430.0mg, 1.73 mmol) in THF (5 mL) was added n-butyllithium (2.36 M, 2.35 mL)at −78° C., and upon addition the temperature was increased to −40° C.and the reaction mixture was stirred 30 minutes. tert-Butyl4-(4-formylpyrazol-1-yl)-4-methyl-piperidine-1-carboxylate 2 (508.50 mg,1.73 mmol) in THF (5 mL) was added at −78° C., and then the reactionmixture was warmed to room temperature and stirred for 16 hours. Thereaction mixture was quenched with ammonium chloride solution, dilutedwith ethyl acetate, and washed with water, and the organic layer wasseparated. The organic phase was dried over anhydrous sodium sulfate andevaporated under reduced pressure to obtain the crude compound which waspurified by flash chromatography (using 0%-5% MeOH-DCM) to affordtert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methyl-piperidine-1-carboxylate3 (75 mg, 162.15 μmol, 9.35% yield) as a brown solid. LC MS: ES+ 445.5(−18 due to deoxygenated fragment).

Step 2: Preparation of Trifluoroacetic Acid Salt of6-((1-(4-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one(4): To a stirred solution of6-[[1-(4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one3 (75.0 mg, 162.15 μmol) in DCE (1 mL) was added triethylsilane (75.42mg, 648.59 μmol, 103.59 μL) and trifluoroacetic acid (147.91 mg, 1.30mmol, 99.94 and the reaction mixture was stirred at 80° C. for 2 hours.The reaction was concentrated under reduced pressure and triturated withdiethyl ether to afford[4-methyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-piperidyl]2,2,2-trifluoroacetate4 (72 mg, 156.37 μmol, 96.44% yield) as a brown gummy solid. LC MS: ES+347.2.

Step 3: Preparation of tert-Butyl4-Methyl-4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(5): To a stirred solution of[4-methyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-piperidyl]2,2,2-trifluoroacetate4 (72.0 mg, 156.37 μmol) in DCM (6 mL) was added triethylamine (47.47mg, 469.11 μmol, 65.38 μL) with cooling followed by di-tert-butyldicarbonate (51.19 mg, 234.55 μmol, 53.83 and the reaction was stirredat room temperature for 16 hours. The reaction mixture was diluted withethyl acetate, washed with water and brine solution, and the organiclayer was separated. The organic phase was dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crude whichwas purified by flash chromatography (using 0%-5% MeOH-DCM to affordtert-butyl4-methyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate5 (40.0 mg, 89.58 μmol, 57.29% yield) as yellow sticky solid. LC MS: ES+447.4.

Step 4: Preparation of6-((1-(4-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-onehydrochloride (6): To a stirred solution of tert-butyl4-methyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate5 (40.0 mg, 89.58 μmol) in 1,4-dioxane (1 mL) was added hydrochloricacid in dioxane (89.58 μmol, 2 mL), and the reaction was stirred at roomtemperature for 2 hours. The solvent was evaporated under reducedpressure, and the crude was washed with ether and pentane to afford6-[[1-(1-chloro-4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one6 (34 mg, 88.80 μmol, 99.13% yield) as yellow solid. LC MS: ES+ 347.4.

Step 5: Preparation of6-((1-(1-(Cubane-1-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one(8): To a stirred solution of6-[[1-(1-chloro-4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one6 (34.0 mg, 88.80 μmol) in DMF (1 mL) was addedN,N-diisopropylethylamine (34.43 mg, 266.40 μmol, 46.40 μL) with coolingfollowed by cubane-1-carboxylic acid 7 (13.16 mg, 88.80 μmol) and HATU(50.65 mg, 133.20 μmol), and the reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was diluted with ethylacetate and washed with sodium bicarbonate solution, water and brinesolution. The organic fraction was separated, dried over anhydroussodium sulfate and evaporated under reduced pressure to obtain the crudecompound, which was purified by preparative TLC plate (eluting with 3%MeOH-DCM) to afford6-[[1-[1-(cubane-1-carbonyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one8 (20.0 mg, 41.97 μmol, 47.26% yield) as yellow solid. LC MS: ES+ 477.3.

Step 6: Preparation of3-(6-((1-(1-(Cubane-1-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 18): To a stirred solution6-[[1-[1-(cubane-1-carbonyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one8 (20.0 mg, 41.97 μmol) in DMF (1 mL) was added sodium hydride (60%dispersion in mineral oil, 3.22 mg, 83.93 μmol) with cooling, and thereaction was heated at 60° C. for 30 minutes.3-Bromopiperidine-2,6-dione 9 (8.06 mg, 41.97 μmol) was added withheating, and the reaction was continued for 4 hours at 60° C. TLC showedconsumption of 9, so 3-bromopiperidine-2,6-dione (8.06 mg, 41.97 μmol)was further added, and the reaction mixture was heated at 60° C. for 16hours. The reaction mixture was diluted with ethyl acetate, washed withwater and the organic fraction was separated. The organic phase was thendried over anhydrous sodium sulfate and evaporated under reducedpressure to obtain the crude compound, which was purified by preparativeTLC plate (eluting with 40% ethyl acetate-DCM) to afford3-[6-[[1-[1-(cubane-1-carbonyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 18) (7 mg, 11.75 nmol, 27.99% yield, 98.62% purity) as ayellow solid. ¹H NMR (d6-DMSO, 400 MHZ) δ 11.10 (s, 1H), 8.39 (d, J=8.28Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.84 (d, J=7.52 Hz, 1H), 7.81 (s, 1H),7.36-7.33 (m, 2H), 7.07 (d, J=7.32 Hz, 1H), 5.43 (dd, J=12.68, 5.16 Hz,1H), 4.21 (s, 2H), 4.15 (br s, 3H), 3.96 (br s, 4H), 3.74-3.70 (m, 1H),3.23-3.18 (m, 1H), 3.05-2.88 (m, 3H), 2.80-2.72 (m, 1H), 2.66-2.62 (m,1H), 2.40-2.27 (m, 2H), 2.10-2.07 (m, 1H), 1.86-1.71 (m, 2H), 1.34 (s,3H); LC MS: ES+ 588.5.

Example 17. Synthesis of3-(6-((1-(4-Methyl-1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 19)

Step 1: Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carboxylate(3): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 2 (1equiv.) in THF is added butyllithium (2.2 equiv.) at −78° C., and uponaddition the temperature is allowed to increase to −40° C. and isstirred for 30 minutes. 1 (1 equiv.) in THF is added at −78° C., and thereaction mixture is allowed to warm to room temperature and is stirredfor 16 hours. The reaction mixture is quenched with saturated aqueousammonium chloride solution and diluted with ethyl acetate. The Layersare separated, and the organic layer is washed with water. The organicphase is dried over anhydrous sodium sulfate and evaporated underreduced pressure to obtain the crude compound which is purified by flashchromatography using 0-5% MeOH-DCM to afford desired product 3.

Step 2: Synthesis of3-(6-((1-(4-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(4): To a stirred solution of 3 in dioxane is added hydrochloric acid indioxane (10 eq) and the reaction is stirred at room temperature for 2hours. TLC is checked for complete consumption of the starting material.The solvent in the reaction mixture is evaporated under reduced pressureand washed with ether and pentane to afford 4 as solid.

Step 3: Synthesis of3-(6-((1-(4-Methyl-1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 19): To a stirred solution of 4 and1-methylcyclobutane-1-carboxylic acid 5 (1 equiv) in DMF (2 mL) is addedHATU (1.5 equiv.) and DIPEA (3 equiv.), and the reaction mixture isstirred at 25° C. for 16 hr. The reaction mixture is diluted with ethylacetate and washed with water. The organic layer is separated, driedover sodium sulfate, and concentrated under reduced pressure to give thecrude. This crude is purified by silica gel column chromatography togive Compound 19 as a solid.

Example 18. Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)(hydroxy)methyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carboxylate(Compound 20)

Step 1: Synthesis of tert-Butyl4-Methyl-4-(4-(2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(2): To a stirred solution of 1 in DCM is added manganese dioxide (10equiv.) at room temperature, and the reaction is stirred overnight.After completion, the reaction mixture is filtered, and the filtratepart is evaporated under reduced pressure. The crude material is thenpurified by column chromatography to afford 2.

Step 2: Synthesis of tert-Butyl4-(4-(1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carboxylate(4): To a stirred solution of compound 2 in THF is added sodium hydride(60% dispersion in mineral oil, 1 equiv.), and the reaction mixture isrefluxed at 60° C. for 30 minutes. A solution of(3-bromopiperidine-2,6-dione) 3 (0.5 equiv.) in THF is also heated at60° C. After 30 minutes, the first suspension is added to the secondsolution with heating, and the heating is continued for 3 hours. Thereaction mixture is diluted with ethyl acetate and washed with water andbrine solution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound is then purified by flash chromatography toobtain 4.

Step 3: Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)(hydroxy)methyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carboxylate(Compound 20): To a stirred solution of 4 in dry dichloroethane is addedsodium cyanoborohydride (2 equiv.) at 0° C. and the reaction mixture isstirred at 0° C. for 2 h. The reaction is warmed to rt over the periodof 1 h and stirred at rt for 12 h. The completion of the reaction isconfirmed by TLC. The reaction mixture is quenched with water (25 mL)and extracted with DCM (2×25 mL). The combine organic layer is furtherwashed with brine (1×25 mL), dried over anhydrous Na₂SO₄, concentratedto provide the crude product Compound 20.

Example 19. Synthesis of3-(6-((1-(4-Methyl-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 21)

Step 1: Synthesis of6-((1-(4-Methyl-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one(3): To a stirred solution of 1 in THF in a microwave vial is added1-methylcyclobutane-1-carbaldehyde 2 (1 equiv.) followed by the additionof dibutyltin dichloride (2 equiv.), and the reaction is stirred for 1hour at rt. Phenylsilane (1 equiv) is added to the mixture, and thereaction mixture is irradiated in a microwave for 2 hr. The completionof the reaction is confirmed by TLC. The reaction mixture is quenchedwith water (25 mL) and extracted with DCM (2×25 mL). The combine organiclayer is further washed with brine (1×25 mL), dried over anhydrousNa₂SO₄, and concentrated to provide the crude product 3.

Step 2: Synthesis of3-(6-((1-(4-Methyl-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 21): To a stirred solution of 3 in THF is added sodium hydride(60% dispersion in mineral oil, 1 equiv.), and the reaction mixture isrefluxed at 60° C. for 30 minutes. A solution of(3-bromopiperidine-2,6-dione) (0.5 equiv.) in THF is also heated at 60°C. After 30 minutes, the first suspension is added to the secondsolution with heating, and the heating is continued for 3 hours. Thereaction mixture is diluted with ethyl acetate and washed with water andbrine solution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound is then purified by flash chromatography toobtain Compound 21.

Example 20: Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 22) and3-(6-((1-(1-(Cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxopyrrolo[4,3,2-ij]isoquinolin-1(2H)-yl)piperidine-2,6-dione(Compound 23)

Step 1: Synthesis of 6-Bromopyrrolo[4,3,2-ij]isoquinolin-2(1H)-one (2):To a stirred solution of triphosgene (332.58 mg, 1.12 mmol) in DCM (10mL) was added pyridine (620.55 mg, 7.85 mmol, 634.51 μL) at −15° C., andthe reaction was stirred for 10 minutes. 4-bromoisoquinolin-1-amine 1(500 mg, 2.24 mmol) was added at −15° C., and the reaction was graduallywarmed to rt and stirred for 6 h. Aluminum chloride (298.88 mg, 2.24mmol, 122.49 μL) was added to the reaction mixture, and it was stirredat RT for 16 h. It was diluted with water, extracted with ethyl acetate,and washed with water and brine. The organic layer was dried over sodiumsulfate and concentrated under reduced pressure. The crude was purifiedby CombiFlash eluting with 25% ethyl acetate in hexane to afford 155 mgof 2.

Step 2: Synthesis of tert-Butyl4-(4-(Hydroxy(2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(4): To a stirred solution of6-bromopyrrolo[4,3,2-ij]isoquinolin-2(1H)-one 2 (1 equiv.) in THF isadded butyllithium (2.2 equiv.) at −78° C. After the addition iscomplete the temperature is allowed to increase to −40° C., and thereaction mixture is stirred at the same temperature for 30 minutes. 3 (1equiv.) in THF is added at −78° C., and then the reaction mixture isallowed to warm to room temperature and is stirred for 16 hours. Thereaction mixture is quenched with saturated aqueous ammonium chloridesolution and diluted with ethyl acetate. The layers are separated, andthe organic phase is washed with water. The organic layer is then driedover anhydrous sodium sulfate and evaporated under reduced pressure toobtain the crude compound which is purified by flash chromatographyusing 0-5% MeOH-DCM to afford desired product 4.

Step 3: Synthesis of tert-Butyl4-(4-((2-Oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(5): To a stirred solution of 4 in DCE is added triethylsilane (2equiv.) and trifluoroacetic acid (5 equiv.), and the reaction is stirredfor 30 minutes under microwave irradiation at 70° C. The solvent in thereaction mixture is evaporated under reduced pressure to obtain thecrude which is washed with ether and pentane to afford 5.

Step 4: Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 22): To a stirred solution of compound 5 in THF is addedsodium hydride (60% dispersion in mineral oil, 1 equiv.), and thereaction mixture is refluxed at 60° C. for 30 minutes. A solution of(3-bromopiperidine-2,6-dione) 6 (0.5 equiv.) in THF is also heated at60° C. After 30 minutes the first suspension is added to the secondsolution with heating, and the heating is continued for 3 hours. Thereaction mixture is diluted with ethyl acetate and washed with water andbrine solution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound is then purified by flash chromatography toobtain Compound 22.

Step 5: Synthesis of3-(2-Oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)pyrrolo[4,3,2-ij]isoquinolin-1(2H)-yl)piperidine-2,6-dione(7): To a stirred solution of Compound 22 in dioxane is addedhydrochloric acid in dioxane (10 equiv.), and the reaction is stirred atroom temperature for 2 hours. Upon completion of the reaction asdetermined by TLC, the solvent in the reaction mixture is evaporatedunder reduced pressure and washed with ether and pentane to afford 7.

Step 6: Synthesis of3-(6-((1-(1-(Cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxopyrrolo[4,3,2-ij]isoquinolin-1(2H)-yl)piperidine-2,6-dione(Compound 23): To a stirred solution of 7 and cubane-1-carboxylic acid 8(1 equiv.) in DMF (2 mL) is added HATU (1.5 equiv.) and DIPEA (3equiv.), and the reaction mixture is stirred at 25° C. for 16 hr. WhenLCMS shows the desired mass, the reaction mixture is diluted with ethylacetate and washed with water. The organic layer is separated, driedover sodium sulfate and concentrated under reduced pressure to give thecrude Compound 23. This crude is purified by prep-TLC (using 100% ethylacetate) to give Compound 23 as solid.

Example 21. Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 24) and3-(6-((1-(1-(Cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione(Compound 25)

Step 1: Synthesis of 6-Bromopyrrolo[2,3,4-de]isoquinolin-2(1H)-one (2):To a stirred solution of triphosgene (0.5 equiv.) in DCM is addedpyridine (3 equiv.) at −15° C., and the reaction is stirred for 10minutes. 1-bromoisoquinolin-4-amine 1 (1 equiv.) is added at −15° C.,and the reaction is gradually warmed to rt and stirred for 6 h. Aluminumchloride (1 equiv) is added to the reaction mixture and the reaction isstirred at rt for 16 h. The reaction is diluted with water, extractedwith ethyl acetate, and washed with water and brine. The reaction isthen dried over sodium sulfate and concentrated under reduced pressure.The crude is purified by CombiFlash eluting at 25% ethyl acetate inhexane to afford 2.

Step 2: Synthesis of tert-Butyl4-(4-(Hydroxy(2-oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(4): To a stirred solution of6-bromopyrrolo[2,3,4-de]isoquinolin-2(1H)-one 2 (1 equiv.) in THF isadded butyllithium (2.2 equiv.) at −78° C. Upon addition the temperatureis allowed to increase to −40° C. and the reaction mixture is stirred atthe same temperature for 30 minutes. 3 (1 equiv.) in THF is added at−78° C. and then the reaction mixture is allowed to warm to roomtemperature and is stirred for 16 hours. The reaction mixture isquenched with saturated aqueous ammonium chloride solution and dilutedwith ethyl acetate. The layers are separated, and the organic layer iswashed with water. The combined organic layers are then dried overanhydrous sodium sulfate and evaporated under reduced pressure to obtainthe crude compound which is purified by flash chromatography using 0-5%MeOH-DCM to afford desired product 4.

Step 3: Synthesis of tert-Butyl4-(4-((2-Oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(5): To a stirred solution of 4 in DCE is added triethylsilane (2equiv.) and trifluoroacetic acid (5 equiv.), and the reaction is stirredfor 30 minutes under microwave irradiation at 70° C. The solvent in thereaction mixture is evaporated under reduced pressure to obtain thecrude which is washed with ether and pentane to afford 5.

Step 4: Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 24): To a stirred solution of compound 5 in DMF is addedsodium hydride (60% dispersion in mineral oil, 1 equiv.), and thereaction mixture is refluxed at 60° C. for 30 minutes. A solution of3-bromopiperidine-2,6-dione 6 (0.5 equiv.) in DMF is also heated at 60°C. After 30 minutes the first suspension is added to the second solutionwith heating, and the heating is continued for 3 hours. The reactionmixture is diluted with ethyl acetate and washed with water and brinesolution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to provide the crudecompound. The crude compound is then purified by flash chromatography toprovide Compound 24.

Step 5: Synthesis of3-(2-Oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)pyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione(7): To a stirred solution of Compound 24 in dioxane is addedhydrochloric acid in dioxane (10 equiv.), and the reaction is stirred atroom temperature for 2 hours. Upon consumption of the SM as determinedby TLC, the solvent in the reaction mixture is evaporated under reducedpressure and washed with ether and pentane to afford 7 as solid.

Step 6: Synthesis of3-(6-((1-(1-(Cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione(Compound 25): To a stirred solution of 7 and cubane-1-carboxylic acid 8(1 equiv.) in DMF (2 mL) is added HATU (1.5 equiv.) and DIPEA (3equiv.), and the reaction mixture is stirred at 25° C. for 16 hr. WhenLCMS shows desired mass, the reaction mixture is diluted with ethylacetate and washed with water. The organic layer is separated, driedover sodium sulfate and concentrated under reduced pressure to give thecrude. This crude is purified by prep-TLC (using 100% ethyl acetate) togive Compound 25 as solid.

Example 22. Synthesis of3-(6-((4-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 26)

Step 1: Synthesis of 4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(2): To a stirred solution of 4-bromo-1H-pyrazole 1 (3.0 g, 20.41 mmol)in 3,4-dihydro-2H-pyran (2.58 g, 30.62 mmol, 2.78 mL) at 0° C. was addedtrifluoroacetic acid (116.37 mg, 1.02 mmol, 78.63 μL) drop-wise, and thereaction was stirred at 80° C. overnight. Upon consumption of thestarting material as determined by TLC, the reaction mixture was dilutedwith DCM and washed with 1M NaOH solution. The reaction mixture wasdried over Na₂SO₄, filtered, and evaporated under vacuum. The crude waspurified by CombiFlash to get the pure compound4-bromo-1-tetrahydropyran-2-yl-pyrazole 2 (3.44 g, 14.89 mmol, 72.93%yield).

Step 2: Synthesis of1-Benzyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1,2,3,6-tetrahydropyridine(4): To a stirred solution of 4-bromo-1-tetrahydropyran-2-yl-pyrazole 2(700 mg, 3.03 mmol) in water (4.0 mL) and DMF (16.0 mL) was added sodiumcarbonate (642.11 mg, 6.06 mmol, 253.80 μL) and1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine3 (1.09 g, 3.63 mmol), and the reaction mixture was degassed with argonfor 10 mins. Then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride dichloromethane (247.37 mg, 302.91 mol) was added, and thereaction mixture was stirred at 100° C. overnight in a sealed tube. Uponcomplete consumption of SM as determined by TLC, the reaction mixturewas diluted with ethyl acetate and washed with water and brine solution.The organic layer was dried over Na₂SO₄ and filtered. The reactionmixture was evaporated under vacuum, and the crude was purified byCombiFlash to get the pure compound1-benzyl-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-3,6-dihydro-2H-pyridine4 (230 mg, 711.13 mol, 23.48% yield).

Step 3: Synthesis of4-(1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)piperidine (5): Astirred solution of 4 in ethanol is degassed with argon for 10 minutes.10% Pd/C (30 Wt %) is added to the reaction mixture, and it is subjectedto hydrogenation under a hydrogen balloon for 16 hours. The reactionmixture is filtered through celite and concentrated under reducedpressure to obtain 5 as desired product.

Step 4: Synthesis of(1-Methylcyclobutyl)(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)methanone(7): To a stirred solution of 1-methylcyclobutanecarboxylic acid 6(194.26 mg, 1.70 mmol) in DMF (2.0 mL) was addedN-ethyl-N-isopropyl-propan-2-amine 5 (439.91 mg, 3.40 mmol, 592.87 andthe reaction mixture was stirred at rt for 5 mins. HATU (647.12 mg, 1.70mmol) was added, and the reaction mixture was stirred for another 5mins. After that 4-(1-tetrahydropyran-2-ylpyrazol-4-yl)piperidine 5 (267mg, 1.13 mmol) in DMF (2.0 mL) was added to the reaction mixturedrop-wise, the reaction mixture was stirred at rt for overnight. Uponconsumption of the SM as determined by TLC, the reaction mix was dilutedwith ethyl acetate and washed with cold NaHCO₃ solution. The reactionmix was dried over Na₂SO₄, filtered, and concentrated under reducepressure to provide crude product which was purified by columnchromatography to provide 7.

Step 5: Synthesis of(4-(1H-Pyrazol-4-yl)piperidin-1-yl)(1-methylcyclobutyl)methanone (8): Toa stirred solution of(1-methylcyclobutyl)(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)methanone7 in dioxane is added 4M HCl in dioxane (2 equiv.), and the reaction isstirred at RT for 1 h. The solution is concentrated under reducedpressure to afford(4-(1H-pyrazol-4-yl)piperidin-1-yl)(1-methylcyclobutyl)methanone 8 assolid.

Step 6:1-Allyl-6-((4-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-1-yl)methyl)benzo[cd]indol-2(1H)-one(10): A magnetically stirred solution of 8 (1.2 equiv.) and 9 (1 equiv.)in DMF is treated with Cs₂CO₃ (2.5 equiv.) and stirred at RT for 4 h.The reaction is monitored over a period of 24 h (temp 25-50° C.) via TLCand LC-MS. After consumption of SM, the reaction mixture is washed withwater. The phases are separated, and the aqueous layer is furtherextracted with EtOAc. The organic layers are combined, dried over MgSO₄,and filtered. The solvents are removed under reduced pressure to give aresidue, which is purified by column chromatography (eluted with 80%EA/Hex) to yield product 10 as a white solid.

Step 7: Synthesis of6-((4-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-1-yl)methyl)benzo[cd]indol-2(1H)-one(11): A solution of 10 (1 equiv.) in dry DCM is added to a mixture ofPd(PPh₃)₄ (10%) and 1,3 dimethyl barbituric acid (3 equiv.) under argon.The reaction mixture is stirred for 5 h at 35° C., quenched withsaturated aqueous NaHCO₃, and extracted with CH₂Cl₂. The combinedorganic layers are dried over MgSO₄, filtered, and concentrated. Thecrude is purified by column chromatography in 100-200 Silica in 3-4%MeOH in DCM to afford the desired compound 11 as solid.

Step 8: Synthesis of3-(6-((4-(1-(1-Methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 26): To the stirred solution of compound 11 in DMF is addedsodium hydride (60% dispersion in mineral oil, 1 equiv.), and thereaction mixture is refluxed at 60° C. for 30 minutes. A solution of3-bromopiperidine-2,6-dione (0.5 equiv.) in DMF is also heated at 60° C.After 30 minutes the first suspension is added to the second solutionwith heating, and the heating is continued for 3 hours. The reactionmixture is diluted with ethyl acetate and washed with water and brinesolution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound is then purified by flash chromatography toobtain Compound 26.

Example 23. Synthesis of4-(4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile(Compound 27)

Step 1: Synthesis of3-Fluoro-4-(4-(4-(hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)benzonitrile(3): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 2 (1equiv.) in THF is added butyllithium (2.2 equiv.) at −78° C. Uponaddition, the temperature is allowed to increase to −40° C. and thereaction mixture is stirred at the same temperature for 30 minutes.3-fluoro-4-(4-(4-formylbenzyl)piperazin-1-yl)benzonitrile 1 (1 equiv.)in THF at −78° C., and then the reaction mixture is allowed to warm toroom temperature and is stirred for 16 hours. The reaction mixture isquenched with saturated aqueous ammonium chloride solution and dilutedwith ethyl acetate. The layers are separated, and the organic layer iswashed with water. The organics are then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound which is purified by flash chromatography using 0-5% MeOH-DCMto afford desired product 3.

Step 2: Synthesis of3-Fluoro-4-(4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)benzonitrile(4): To the stirred solution of 3 in DCE is added triethylsilane (3equiv.) and trifluoroacetic acid (10 equiv.), and the reaction isstirred for 30 minutes under microwave irradiation at 70° C. The solventin the reaction mixture is evaporated under reduced pressure to obtainthe crude which is washed with ether and pentane to afford 4 as browngum in the form of crude.

Step 3: Synthesis of4-(4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile(Compound 27): To a stirred solution of compound 4 in THF is addedsodium hydride (60% dispersion in mineral oil, 1 equiv.), and thereaction mixture is refluxed at 60° C. for 30 minutes. A solution of(3-bromopiperidine-2,6-dione) 5 (0.5 equiv.) in THF is also heated at60° C. After 30 minutes the first suspension is added to the secondsolution with heating, and the heating is continued for 3 hours. Thereaction mixture is diluted with ethyl acetate and washed with water andbrine solution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound is then purified by flash chromatography toobtain Compound 27.

Example 24. Synthesis of3-(6-((1-(1-(Cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-2-oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione(Compound 28)

Step 1: Synthesis of tert-Butyl4-(4-((2-Oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(3): To a stirred solution of tert-butyl4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate 2 (1 equiv.) and6-bromopyrrolo[2,3,4-de]isoquinolin-2(1H)-one 1 (1 equiv.) intoluene ina sealed tube is added cesium carbonate (2.5 equiv.), and the reactionmixture is degassed for 5 min under argon atmosphere. Then pd₂(dba)₃(10%) and Xantphos (20%) are added, and the solution is again purged for2 min under argon atmosphere. Thereafter, the reaction mixture is heatedto 90° C. for 16 hr. After consumption of SM is noted, the reactionmixture is filtered through a celite bed and concentrated in vacuo.Purification by CombiFlash column chromatography (eluted by 15% ethylacetate in n-hexane) gives the title compound 3.

Step 2: tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(5): To a stirred solution of compound 3 in DMF is added Sodium hydride(60% dispersion in mineral oil, 1 equiv.), and the reaction mixture isrefluxed at 60° C. for 30 minutes. A solution of(3-bromopiperidine-2,6-dione) 4 (0.5 equiv.) in DMF is also heated at60° C. After 30 minutes the first suspension is added to the secondsolution with heating, and the heating is continued for 3 hours. Thereaction mixture is diluted with ethyl acetate and washed with water andbrine solution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound is then purified by flash chromatography toobtain 5.

Step 3: Synthesis of3-(2-Oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrrolo[de]isoquinolin-1(2H)-yl)piperidine-2,6-dione(6): To the stirred solution of 5 in dioxane is added hydrochloric acidin dioxane (10 equiv.), and the reaction is stirred at room temperaturefor 2 hours. TLC is checked until complete consumption of the startingmaterial is noted. At that point, the solvent in the reaction mixture isevaporated under reduced pressure and washed with ether and pentane toafford 6.

Step 4: Synthesis of3-(6-((1-(1-(Cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-2-oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione(Compound 28): To a stirred solution of 6 and cubane-1-carboxylic acid 7(1 equiv.) in DMF (2 mL) is added HATU (1.5 equiv.) and DIPEA (3equiv.), and the reaction mixture is stirred at 25° C. for 16 hr.According to LCMS, when desired mass is observed, the reaction mixtureis diluted with ethyl acetate and washed with water. The organic layeris separated, dried over sodium sulfate and concentrated under reducedpressure to give the crude. This crude is purified by prep-TLC (using100% ethyl acetate) to give Compound 28 as a solid.

Example 25. Synthesis of3-(6-Hydroxy-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound29), tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)oxy)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 30), and3-(6-((1-(1-((2r,3r,5r,6r,7r,8r)-Cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)oxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 31)

Step 1: Synthesis of1-(2,6-Bis(benzyloxy)pyridin-3-yl)-6-bromobenzo[cd]indol-2(1H)-one (3):To a stirred solution of 2,6-dibenzyloxy-3-iodo-pyridine 2 (1 equiv.)and 6-bromobenzo[cd]indol-2(1H)-one 1 (1.2 equiv.) in dioxane is addedtribasic potassium phosphate (1 equiv.), and the reaction mixture isdegassed for 10 mins. Subsequently, (1R,2R)-(−)-1,2-diaminocyclohexane(0.1 equiv.) is added followed by copper (I) iodide (2%). and again thesolution is degassed for 5 mins. The reaction mixture is then stirred at100° C. for 16 hr. The reaction mixture is then allowed to come to RTand is extracted with ethyl acetate. The organic phase is washed withbrine and dried over anhyd. Na₂SO₄. The solvent is evaporated and theresidue is purified by column chromatography (eluted with 40%Ethylacetate in Hexane) on silica gel to furnish the desired product1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromobenzo[cd]indol-2(1H)-one 3 assolid.

Step 2: Synthesis of1-(2,6-Bis(benzyloxy)pyridin-3-yl)-6-hydroxybenzo[cd]indol-2(1H)-one(4): To the stirred solution of1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromobenzo[cd]indol-2(1H)-one 3 indioxane (8 mL) and water (2 mL) is added potassium Hydroxide (2 equiv.),and the resulting solution is degassed with N₂ for 15 minutes followedby the addition of (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium(5%) and Tert-Butyl Xphos-2-Di-tert-butylphosphino-2′,4′,6 (15%). Thereaction mixture is further heated at 100° C. in a sealed tube for 12hr. After formation of desired pdt as evidence from LCMS, the reactionmixture is filtered through a celite bed and washed with ethyl acetate.The combined organic layers are separated and evaporated. The cruderesidue is purified by column chromatography to afford1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-hydroxybenzo[cd]indol-2(1H)-one 4as solid.

Step 3: Synthesis of3-(6-Hydroxy-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound29): A solution of1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-hydroxybenzo[cd]indol-2(1H)-one 4in ethyl acetate/Ethanol (1/1) was hydrogenated using Palladium, 10% oncarbon, Type 487, (10%) under balloon pressure for 12 hr at rt. Aftercompletion of reaction, the reaction mixture is filtered through acelite bed and washed with ethyl acetate several times. The filtrate iscollected and concentrated under reduced pressure to afford3-(6-hydroxy-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound29) as crude product.

Step 4: Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)oxy)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 30): After standard cycles of evacuation and back-filling withdry and pure nitrogen, an oven-dried Schlenk tube equipped with amagnetic stirring bar is charged with Cu₂O (0.1 mmol),rel-(1R,2R)—N¹,N²-Bis(2-pyridinylmethylene)-1,2-cyclohexanediamine (0.4mmol), Cs₂CO₃ (4.0 mmol), activated and powdered 3 Å molecular sieves(600 mg), 3-(6-hydroxy-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dioneCompound 29 (2.0 mmol), and tert-butyl4-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate 5 (3.0 mmol), if asolid. The tube is evacuated, back-filled with nitrogen and capped witha rubber septum. If liquids, the phenol and the aryl halide are addedunder a stream of nitrogen by syringe at room temperature, followed byanhydrous and degassed acetonitrile or DMF (1.2 mL). The septum isremoved, the tube is sealed under a positive pressure of nitrogen andstirred in an oil bath (preheated to 82° C. or 110° C.) for the requiredtime period. The reaction mixture is allowed to cool to roomtemperature, diluted with dichloromethane and filtered through a plug ofCelite®, the filter cake being further washed with dichloromethane (20mL). The filtrate is concentrated in vacuo to yield the crude productthat is purified by silica gel chromatography to provide Compound 30.

Step 5: Synthesis of3-(2-Oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)oxy)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(6): To a stirred solution of Compound 30 in dioxane is addedhydrochloric acid in dioxane (10 equiv.), and the reaction is stirred atroom temperature for 2 hours. TLC is checked for complete consumption ofthe starting material. The solvent in the reaction mixture is evaporatedunder reduced pressure and washed with ether and pentane to afford 6 asa solid.

Step 6: Synthesis of3-(6-((1-(1-((2r,3r,5r,6r,7r,8r)-Cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)oxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 31): To a stirred solution of 6 and cubane-1-carboxylic acid(1 equiv.) in DMF (2 mL) is added HATU (1.5 equiv.) and DIPEA (3equiv.), and the reaction mixture is stirred at 25° C. for 16 hr.According to LCMS, when the desired mass is observed, the reactionmixture is diluted with ethyl acetate and washed with water. The organiclayer is separated, dried over sodium sulfate and concentrated underreduced pressure to give the crude. This crude is purified by silica gelchromatography to give Compound 31 as a solid.

Example 26. Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)oxy)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 32)

Step 1: Synthesis of1-(2,6-Bis(benzyloxy)pyridin-3-yl)-6-bromopyrrolo[2,3,4-de]isoquinolin-2(1H)-one(3): To a stirred solution of 2,6-dibenzyloxy-3-iodo-pyridine 2 (1equiv.) and 6-bromopyrrolo[2,3,4-de]isoquinolin-2(1H)-one 1 (1.2 equiv.)in dioxane is added tribasic potassium phosphate (1 equiv.), and thesolution is degassed for 10 mins. Subsequently,(1R,2R)-(−)-1,2-diaminocyclohexane (0.1 equiv.) is added followed bycopper (I) iodide (2%), and again the solution is degassed for 5 mins.The reaction mixture is then stirred at 100° C. for 16 hr. The reactionmixture is then allowed to come to RT and is extracted with ethylacetate. The organic phase is washed with brine, and finally dried overanhyd. Na₂SO₄. The solvent is evaporated and the residue is purified bycolumn chromatography (eluted with 40% Ethylacetate in Hexane) on silicagel to furnish the desired product1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromopyrrolo[2,3,4-de]isoquinolin-2(1H)-one3 as solid.

Step 2: Synthesis of1-(2,6-Bis(benzyloxy)pyridin-3-yl)-6-hydroxypyrrolo[2,3,4-de]isoquinolin-2(1H)-one(4): To a stirred solution of1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromopyrrolo[2,3,4-de]isoquinolin-2(1H)-one3 in dioxane (8 mL) and water (2 mL) is added potassium hydroxide (2equiv.), and the resulting solution is degassed with N₂ for 15 minutesfollowed by the addition of (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one;palladium (5%) and Tert-Butyl Xphos-2-Di-tert-butylphosphino-2′,4′,6(15%). The reaction mixture is heated at 100° C. in a sealed tube for 12hr. After formation of desired pdt as evidence from LCMS, the reactionmixture is filtered through a celite bed and washed with ethyl acetate.The combined organic layer is separated and evaporated. The cruderesidue is purified by column chromatography to afford1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-hydroxypyrrolo[2,3,4-de]isoquinolin-2(1H)-one4 as solid.

Step 3: Synthesis of3-(6-hydroxy-2-Oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione(5): A solution of1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-hydroxypyrrolo[2,3,4-de]isoquinolin-2(1H)-one4 in ethyl acetate/ethanol (1/1) is hydrogenated using palladium, 10% oncarbon, Type 487, (10%) under balloon pressure for 12 hr at rt. Aftercompletion of the reaction, the reaction mixture is filtered through acelite bed and washed with ethyl acetate several times. The filtrate iscollected and concentrated under reduced pressure to afford3-(6-hydroxy-2-oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione5 as a crude product.

Step 4: Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[2,3,4-de]isoquinolin-6-yl)oxy)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 32): After standard cycles of evacuation and back-filling withdry and pure nitrogen, an oven-dried Schlenk tube equipped with amagnetic stirring bar is charged with Cu₂O (0.1 mmol),rel-(1R,2R)—N¹,N²-Bis(2-pyridinylmethylene)-1,2-cyclohexanediamine (0.4mmol), Cs₂CO₃ (4.0 mmol), activated and powdered 3 Å molecular sieves(600 mg),3-(6-hydroxy-2-oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione(2.0 mmol) 5, and tert-butyl4-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (3.0 mmol) 6, if asolid. The tube is evacuated, back-filled with nitrogen and capped witha rubber septum. If liquids, the phenol and the aryl halide are addedunder a stream of nitrogen by syringe at room temperature, followed byanhydrous and degassed acetonitrile or DMF (1.2 mL). The septum isremoved, the tube sealed under a positive pressure of nitrogen andstirred in an oil bath (preheated to 82° C. or 110° C.), for therequired time period. The reaction mixture is allowed to cool to roomtemperature, diluted with dichloromethane and filtered through a plug ofCelite®, the filter cake is further washed with dichloromethane (20 mL).The filtrate is concentrated in vacuo to yield the crude product, and ispurified by silica gel chromatography to yield Compound 32.

Example 27. Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 33)

Step 1: Synthesis of tert-Butyl4-(4-((2-Oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(3): In a sealed tube a stirred solution of tert-butyl4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate 2 (1 equiv.) and3-(6-bromo-2-oxopyrrolo[4,3,2-ij]isoquinolin-1(2H)-yl)piperidine-2,6-dione1 (1 equiv.) intoluene is added cesium carbonate (2.5 equiv.), and thenthe reaction mixture is degassed for 5 min under an argon atmosphere. Tothe solution is added pd₂(dba)₃ (10%) and Xantphos (20%), and thesolution is purged for 2 min under argon atmosphere/The reaction mixtureis heated to 90° C. for 16 hr. After consumption of SM, the reactionmixture is filtered through a celite bed and concentrated in vacuo.Purification by CombiFlash column chromatography (eluted by 15% ethylacetate in n-hexane) to provides the title compound 3.

Step 2: Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 33): To a stirred solution of compound 3 in DMF is addedsodium hydride (i60% dispersion in mineral oil, 1 equiv.), and thereaction mixture is refluxed at 60° C. for 30 minutes. A solution of(3-bromopiperidine-2,6-dione) 4 (0.5 equiv.) in DMF is also heated at60° C. After 30 minutes the first suspension is added to the secondsolution with heating, and the heating is continued for 3 hours. Thereaction mixture is diluted with ethyl acetate and washed with water andbrine solution. The organic fraction is then dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain the crudecompound. The crude compound is then purified by flash chromatography toobtain Compound 33.

Example 28: Synthesis of tert-Butyl4-(4-((1-(2,6-Dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)oxy)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 34)

A Schlenk tube equipped with a magnetic stirring bar is charged withCu₂O (0.1 mmol),rel-(1R,2R)—N¹,N²-Bis(2-pyridinylmethylene)-1,2-cyclohexanediamine (0.4mmol), Cs₂CO₃ (4.0 mmol), activated and powdered 3 Å molecular sieves(600 mg), tert-butyl4-(4-hydroxy-1H-pyrazol-1-yl)piperidine-1-carboxylate 2 (2.0 mmol), and3-(6-bromo-2-oxopyrrolo[4,3,2-ij]isoquinolin-1(2H)-yl)piperidine-2,6-dione 1 (3.0 mmol), if a solid. Thetube is evacuated, back-filled with nitrogen and capped with a rubberseptum. If liquids, the phenol and the aryl halide were added under astream of nitrogen by syringe at room temperature, followed by anhydrousand degassed acetonitrile or DMF (1.2 mL). The septum is removed, thetube sealed under a positive pressure of nitrogen and stirred in an oilbath (preheated to 110° C.), for the required time period. The reactionmixture is allowed to cool to room temperature, diluted withdichloromethane and filtered through a plug of Celite®, the filter cakebeing further washed with dichloromethane (20 mL). The filtrate isconcentrated in vacuo to yield the crude product that is purified bysilica gel chromatography to yield Compound 33.

Example 29. Synthesis of6-(chloromethyl)-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one (Compound35)

Step 1: Synthesis of 1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one: To astirred solution of 1H-benzo[cd]indol-2-one 1 (25 g, 147.77 mmol) in DMF(500 mL) was added Sodium hydride (in oil dispersion) 60% dispersion inmineral oil (8.14 g, 203.43 mmol, 60% purity) at 0° C. portion wise andstirred for 1 hour at 0° C. After that p-Methoxy benzyl bromide (44.57g, 221.66 mmol, 31.83 mL) was added slowly and reaction mass was stirredat 25° C. for 16 hrs. The progress of the reaction was monitored by TLC,SM was consumed in TLC. Then the reaction mass was quenched in ice-waterat 0° C. and precipitate (solid) formed was filtered through sintered.The solid was then washed with water and diethyl ether and dried throughrotavapor to get 1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 2 (40g, 121.66 mmol, 82.33% yield, 88% purity) as pale yellow solid. LC MS:ES+ 290.4.

Step 2: Synthesis of1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbaldehyde: Tothe stirred solution of DMF (113.68 g, 1.56 mol, 120.42 mL) was addedPhosphorous oxychloride (238.48 g, 1.56 mol, 145.42 mL) at 0° C. andstirred for 1 hr at RT. After that1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 2 (30 g, 103.69 mmol)was added at 0° C. Then the reaction mixture was stirred at roomtemperature again for 1 hr. The reaction mass was then heated at 90° C.for 16 hrs. TLC matched with authentic and starting was consumed. Thereaction mixture was cooled to 25° C. and quenched in ice-water, solidformed was filtered through sintered and washed with water successively.The solid was dried under reduced pressure to afford the crude product.The crude was then purified by column chromatography eluting by DCM/MeOHto afford1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indole-6-carbaldehyde 3 (15g, 44.90 mmol, 43.31% yield, 95% purity). LC MS: ES+ 318.4.

Step 3: Synthesis of6-(hydroxymethyl)-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one: To astirred suspension of1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indole-6-carbaldehyde 3 (10.2g, 32.14 mmol) in Methanol (500 mL) was added Sodium borohydride (6.08g, 160.71 mmol, 5.68 mL) at 0° C. and the reaction mixture was stirredat room temperature for 3 hr. TLC showed consumption of SM and formationof polar spot. The reaction mixture was quenched with cold water (5 mL)and concentrated under reduced pressure to afford yellow solid residue,which was washed with water, filtered and dried under reduced pressureto afford6-(hydroxymethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 4 (10g, 31.31 mmol, 97.42% yield) as off Yellow solid. LC MS: ES+ 320.2.

Step 4: Synthesis of of6-(chloromethyl)-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one: To astirred suspension of6-(hydroxymethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 4 (10g, 31.31 mmol) in DCM (220 mL) was added TEA (9.51 g, 93.94 mmol, 13.09mL) and stirred at 0° C. and thionyl chloride (11.18 g, 93.94 mmol, 6.86mL) was added drop wised. After completion of addition the reactionmixture was stirred at room temperature for overnight. The reactionmixture was concentrated under reduced pressure to get residue, whichwas diluted with EtOAc and neutralized with saturated solution ofNaHCO₃. The layers were separated, organic layer was washed with water,brine, dried with Na₂SO₄ and concentrated under reduced pressure fordryness to afford Compound 35 (8 g, 23.68 mmol, 75.63% yield) as brownsolid. LC MS: ES+ 338.2.

Example 30. Synthesis of3-(2-oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-hydrochloride (Compound 36)

Step 1: Synthesis of tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:To the stirred solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1 (15 g,77.30 mmol) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate 2(21.60 g, 77.30 mmol) in DMF (130.0 mL) was added Cesium carbonate(50.37 g, 154.61 mmol) and then the reaction mass was heated at 80° C.for 16 hours. The reaction mass was then cooled to room temperature andthen it was extracted with ethyl acetate. The organic part was thendried over sodium sulfate and concentrated under reduced pressure toafford the crude material. The crude was then purified by columnchromatography eluting 1.5-2% Methanol in DCM to afford tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate3 (10.0 g, 25.18 mmol, 32.57% yield, 95% purity) as a white solid. LCMS: ES+ 378.1.

Step 2: Synthesis of tert-butyl4-(4-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: To the stirredsolution of6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 4 (3800mg, 11.25 mmol) and tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate3 (6.37 g, 16.87 mmol) in a sealed tube in Ethanol (7 mL), Toluene (14mL) and 4 drops of water was added tripotassium; phosphate (5.97 g,28.12 mmol). The reaction mixture was degassed with argon for 10minutes. Then tris-o-tolylphosphane (684.78 mg, 2.25 mmol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (1.03 g, 1.12 mmol)were added to the reaction mixture and it was heated at 90° C. for 16 h.Reaction mixture was cooled to RT, diluted with ethyl acetate, washedwith water, brine, dried over sodium sulfate and concentrated underreduced pressure. Crude material was purified by column chromatographyeluting at 40% ethyl acetate in hexane to afford tert-butyl4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate5 (4.6 g, 7.82 mmol, 69.55% yield, 94% purity) as yellow solid. LC MS:ES+ 553.4.

Step 3: Synthesis of Preparation of 2,2,2-trifluoroacetaldehyde compoundwith6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one(1:1): To the stirred solution of tert-butyl4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate5 (4.5 g, 8.14 mmol) in TFA (10 mL) was added Trifluoromethanesulfonicacid (6.11 g, 40.71 mmol, 3.57 mL) at 0° C. and the reaction mixture wasstirred at RT for 16 h. Reaction mixture was concentrated under reducedpressure to afford6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 6 (3.63g, 6.51 mmol, 79.89% yield, 80% purity) as brown gum. This crudematerial was forwarded to the next step without further purification, LCMS: ES+ 333.3.

Step 4: Synthesis of tert-butyl4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:To the stirred solution of6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 6 (3.62g, 10.89 mmol) in DCM (10 mL) was added Triethyl amine (3.31 g, 32.67mmol, 4.55 mL), followed by Di-tert-butyl dicarbonate (3.57 g, 16.34mmol, 3.75 mL) at 0° C. The reaction mixture was stirred at RT for 16 h.Reaction mixture was diluted with ethyl acetate, washed with saturatedsodium bicarbonate solution, brine, dried over sodium sulfate andconcentrated under reduced pressure. Crude material was purified bycombi flash eluting at 60% ethyl acetate in hexane to afford tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate7 (3.2 g, 6.73 mmol, 61.82% yield, 91% purity) as yellow solid, LC MS:ES+ 433.4.

Step 5: Synthesis of tert-butyl4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:To the stirred solution of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate7 (1 g, 2.31 mmol) in THF (20 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (924.74 mg, 23.12 mmol, 60%purity) at cold condition and the reaction mixture was stirred at roomtemperature for 10 minutes followed by the addition of3-bromopiperidine-2,6-dione 8 (2.22 g, 11.56 mmol) portion wise. It wasthen stirred at room temperature for 10 minutes and heated at 70° C. for30 minutes. TLC was checked which showed almost complete consumption ofthe starting material and formation of the desired spot. The reactionmixture was diluted with ethyl acetate, washed with cold water and theorganic fraction was separated. It was then dried over anhydrous sodiumsulphate and evaporated under reduced pressure to obtain the crude whichwas washed with ether and pentane to afford tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate9 (1 g, 1.84 mmol, 79.56% yield) as yellow solid, LC MS: ES+ 544.3.

Step 6: Synthesis of3-(2-oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dionehydrochloride: To the stirred solution of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxobenzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate9 (380.0 mg, 699.03 umol) in Dioxane (5 mL) was added Hydrochloric acidin dioxane (699.03 umol, 15.0 mL) and the reaction mixture was stirredat room temperature for 2 hours. TLC was checked which showed completeconsumption of the starting material. The solvent in the reactionmixture was evaporated under reduced pressure to obtain a yellow solidwhich was washed with ether and pentane to afford3-[6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 36 (330.0 mg, 687.56 umol, 98.36% yield) as yellow solid. LCMS: ES+ 444.4.

Example 31. General Synthesis of Compound 37-Compound 54

To an equi-molar mixture of Amine and Acid DMF (6 mL/mmol) were addedHATU (1.5 equiv) and DIPEA (5.0 equiv) at 0° C. The resulting solutionwas stirred at ambient temperature for 16 hours. The reaction mixturewas then diluted with Ethyl acetate and washed with aqueous NaHCO₃solution, water (×3) and brine. The organic layer was then dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. Crude mass wasthen purified by CombiFlash ISCO column, eluting with 2% methanol in DCMto afford 3:

Compound 37

¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.36 Hz, 1H), 8.08(d, J=6.8 Hz, 1H), 7.85-7.81 (m, 1H), 7.58 (s, 1H), 7.35 (d, J=7.32 Hz,1H), 7.32 (s, 1H), 7.07 (d, J=7.56 Hz, 1H), 4.40 (s, 2H), 4.31-4.30 (m,1H), 4.18 (s, 2H), 3.70-3.66 (m, 3H), 3.13-3.12 (m, 1H), 3.00-2.92 (m,2H), 2.75-2.67 (m, 2H), 2.09-2.07 (m, 2H), 1.97-1.95 (m, 2H), 1.74-1.72(m, 3H), 1.26-1.24 (m, 2H); LC MS: ES+ 554.5.

Compound 38

Yellow solid, 105.0 mg, 45.54% yield, 96.98% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.83 (t, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.36 (d, J=7.4 Hz, 1H), 7.33(s, 1H), 7.07 (d, J=7.24 Hz, 1H), 5.43 (dd, J=12.44, 4.76 Hz, 1H),4.39-4.35 (m, 1H), 4.29-4.25 (m, 2H), 4.19 (s, 2H), 2.97-2.90 (m, 1H),2.79-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.10-2.00 (m, 5H), 1.82-1.80 (m,2H), 1.58-1.57 (m, 2H), 1.50-1.49 (m, 2H); LC MS: ES+ 537.2.

Compound 39

Yellow solid, 145.0 mg, 58.63% yield, 99.73% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.37 (d, J=8.24, 1H), 8.08 (d, J=6.96 Hz, 1H),7.83 (t, J=7.64 Hz, 1H), 7.59 (s, 1H), 7.36 (d, J=7.32 Hz, 1H), 7.33 (s,1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.8, 5.16 Hz, 1H), 4.38-4.34(m, 2H), 4.18 (s, 2H), 3.68-3.65 (m, 1H), 3.26-3.20 (m, 1H), 2.97-2.62(m, 6H), 2.61-2.56 (m, 2H), 2.15-2.08 (m, 2H), 1.99-1.97 (m, 2H),1.90-1.83 (m, 2H), 1.75-1.72 (m, 1H); LC MS: ES+ 551.2.

Compound 40

Yellow solid, 160.0 mg, 66.04% yield, 99.59% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.28 Hz, 1H), 7.83 (t, J=7.62 Hz,1H), 7.60 (s, 1H), 7.36 (d, J=Hz, 1H), 7.33 (s, 1H), 7.07 (d, J=7.28 Hz,1H), 5.43 (dd, J=12.64, 5.08 Hz, 1H), 4.40-4.31 (m, 3H), 4.18 (s, 2H),3.11-2.90 (m, 3H), 2.77-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.09-1.99 (m,3H), 1.83-1.81 (m, 2H), 1.52 (s, 6H); LC MS: ES+ 539.2.

Compound 41

Yellow solid, 34 mg, 44.47% yield, 99.23% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.37 (d, J=8.72 Hz, 1H), 8.08 (d, J=6.92 Hz,1H), 7.83 (t, J=7.28 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.24 Hz, 1H),7.31 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 5.44-5.42 (m, 1H), 4.33-4.30 (m,2H), 4.18 (s, 2H), 3.62-3.61 (m, 2H), 3.48-3.43 (m, 2H), 2.95-2.87 (m,4H), 2.76-2.73 (m, 1H), 2.66-2.60 (m, 2H), 2.10-2.07 (m, 1H), 1.95-1.94(m, 3H), 1.70-1.64 (m, 2H), 1.44-1.43 (m, 2H), 1.24 (s, 3H); LC MS: ES+570.54.

Compound 42

Yellow solid, 35 mg, 45.94% yield, 95.90% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.65 (d, J=4.36 Hz, 2H), 8.36 (d, J=7.68 Hz,1H), 8.08 (d, J=6.88 Hz, 1H), 7.83 (t, J=7.3 Hz, 1H), 7.59 (s, 1H),7.40-7.33 (m, 4H), 7.07 (d, J=7.28 Hz, 1H), 5.44-5.42 (m, 1H), 4.51-4.48(m, 1H), 4.38-4.36 (m, 1H), 4.19 (s, 2H), 3.49-3.45 (m, 1H), 3.23-3.17(m, 1H), 2.95-2.94 (m, 2H), 2.79-2.73 (m, 1H), 2.67-2.63 (m, 1H),2.08-2.07 (m, 2H), 1.87-1.86 (m, 3H); LC MS: ES+ 549.5.

Compound 43

Yellow solid, 44 mg, 60.00% yield, 99.63% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.65-8.61 (m, 2H), 8.37 (d, J=8.24 Hz, 1H),8.08 (d, J=6.96 Hz, 1H), 7.85-7.81 (m, 2H), 7.60 (s, 1H), 7.48-7.45 (m,1H), 7.36 (d, J=7.36 Hz, 1H), 7.33 (s, 1H), 7.07 (d, J=7.28 Hz, 1H),5.43 (dd, J=12.76, 5.16 Hz, 1H), 4.52-4.50 (m, 1H), 4.40-4.34 (m, 1H),4.19 (s, 2H), 3.58-3.57 (m, 1H), 2.97-2.90 (m, 2H), 2.80-2.72 (m, 1H),2.70-2.60 (m, 2H), 2.10-2.07 (m, 2H), 1.95-1.80 (m, 3H); LC MS: ES+549.5.

Compound 44

Yellow solid, 38 mg, 53.21% yield, 98.40% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=7.96 Hz, 1H), 8.08 (d, J=6.92 Hz,1H), 7.83 (t, J=7.8 Hz, 1H), 7.60 (s, 1H), 7.35 (d, J=7.32 Hz, 1H), 7.31(s, 1H), 7.07 (d, J=7.4 Hz, 1H), 5.44-5.42 (m, 1H), 4.33-4.30 (m, 3H),4.18 (s, 2H), 2.92-2.85 (m, 3H), 2.76-2.72 (m, 1H), 2.66-2.57 (m, 1H),2.08-2.06 (m, 1H), 1.96-1.93 (m, 2H), 1.73-1.67 (m, 2H), 1.18 (s, 9H);LC MS: ES+ 528.51.

Compound 45

Yellow solid, 21 mg, 26.89% yield, 98.16% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.82 (t, J=7.64 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.36 Hz, 1H),7.33 (s, 1H), 7.16 (t, J=7.52 Hz, 1H), 7.07-7.04 (m, 3H), 5.43 (dd,J=12.76, 5.24 Hz, 1H), 4.65-4.61 (m, 1H), 4.34-4.33 (m, 1H), 4.18 (s,2H), 3.26-3.23 (m, 1H), 3.13-3.10 (m, 1H), 2.94-2.88 (m, 2H), 2.76-2.72(m, 1H), 2.66-2.62 (m, 1H), 2.20 (s, 3H), 2.11 (s, 3H), 2.07-2.04 (m,2H), 1.89-1.86 (m, 1H), 1.81-1.78 (m, 1H), 1.77-1.66 (m, 1H); LC MS: ES+576.49.

Compound 46

Yellow solid, 32 mg, 43.71% yield, 99.79% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.58-8.57 (m, 1H), 8.37 (d, J=8.2 Hz, 1H),8.08 (d, J=6.96 Hz, 1H), 7.91 (t, J=7.06 Hz, 1H), 7.83 (t, J=7.62 Hz,1H), 7.61 (s, 1H), 7.56 (d, J=7.64 Hz, 1H), 7.48-7.45 (m, 1H), 7.36 (d,J=7.2 Hz, 1H), 7.32 (s, 1H), 7.07 (d, J=7.16 Hz, 1H), 5.44-5.42 (m, 1H),4.55-4.52 (m, 1H), 4.39-4.38 (m, 1H), 4.18 (s, 2H), 3.74-3.70 (m, 1H),3.18-3.12 (m, 1H), 2.96-2.90 (m, 2H), 2.79-2.72 (m, 1H), 2.66-2.62 (m,1H), 2.07-2.03 (m, 2H), 1.86-1.82 (m, 3H); LC MS: ES+ 549.5.

Compound 47

Yellow solid, 32 mg, 43.29% yield, 98.66% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.37 (d, J=8.16 Hz, 1H), 8.08 (d, J=6.92 Hz,1H), 7.83 (t, J=7.58 Hz, 1H), 7.61 (s, 1H), 7.44-7.33 (m, 7H), 7.07 (d,J=7.28 Hz, 1H), 5.44-5.42 (m, 1H), 4.52-4.51 (m, 1H), 4.36-4.35 (m, 1H),4.19 (s, 2H), 3.62-3.61 (m, 1H), 3.15-3.14 (m, 1H), 2.99-2.91 (m, 2H),2.79-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.09-1.80 (m, 5H); LC MS: ES+548.5.

Compound 48

Yellow solid, 55.0 mg, 68.12% yield, 100.00% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=7.96 Hz, 1H), 8.08 (d, J=6.44 Hz,1H), 7.83 (t, J=7.34 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.44 Hz, 1H),7.31 (s, 1H), 7.07 (d, J=7.0 Hz, 1H), 5.44-5.42 (m, 1H), 4.36-4.33 (m,2H), 4.24-4.21 (m, 1H), 4.18 (s, 2H), 3.76 (s, 2H), 3.10-3.08 (m, 1H),2.95-2.93 (m, 2H), 2.85-2.83 (m, 1H), 2.76-2.69 (m, 1H), 2.67-2.62 (m,1H), 2.08-2.01 (m, 1H), 1.99-1.93 (m, 4H), 1.72-1.60 (m, 4H); LC MS: ES+554.2.

Compound 49

Yellow solid, 55.0 mg, 64.65% yield, 99.71% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.36 (d, J=7.92 Hz, 1H), 8.08 (d, J=6.68 Hz,1H), 7.83 (t, J=7.3 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.32(s, 1H), 7.07 (d, J=6.8 Hz, 1H), 5.44-5.42 (m, 1H), 4.33-4.31 (m, 2H),4.18 (s, 2H), 3.97-3.96 (m, 2H), 3.82-3.81 (m, 1H), 3.09-3.08 (m, 1H),2.98-2.91 (m, 1H), 2.79-2.72 (m, 1H), 2.66-2.63 (m, 2H), 2.15-1.90 (m,9H), 1.72-1.64 (m, 2H), 1.12 (s, 3H); LC MS: ES+ 582.3.

Compound 50

Yellow solid, 50.0 mg, 52.01% yield, 98.07% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.08 Hz,1H), 7.83 (t, J=7.48 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=6.96 Hz, 1H),7.31 (s, 1H), 7.07 (d, J=7.16 Hz, 1H), 5.45-5.42 (m, 1H), 4.32-4.26 (m,2H), 4.18 (s, 2H), 3.75-3.73 (m, 1H), 3.06-2.90 (m 2H), 2.76-2.71 (m,1H), 2.66-2.62 (m, 3H), 2.11-2.07 (m, 4H), 1.94-1.92 (m, 2H), 1.82-1.81(m, 4H), 1.72-1.70 (m, 2H), 1.64-1.63 (m, 3H); LC MS: ES+ 566.2.

Compound 51

Yellow solid, 140.0 mg, 60.42% yield, 96.07% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.37 (d, J=7.48 Hz, 1H), 8.08 (d, J=6.28 Hz,1H), 7.83 (t, J=6.82 Hz, 1H), 7.58 (s, 1H), 7.36 (d, J=7.36 Hz, 1H),7.32 (s, 1H), 7.07 (d, J=6.84 Hz, 1H), 5.44-5.42 (m, 1H), 4.42-4.41 (m,1H), 4.34-4.33 (m, 1H), 4.18 (s, 2H), 3.55-3.53 (m, 1H), 3.17-3.12 (m,1H), 2.95-2.91 (m, 1H), 2.77-2.62 (m, 5H), 2.43-2.30 (m, 2H), 2.10-2.07(m, 1H), 1.95-1.94 (m, 3H), 1.76-1.74 (m, 3H); LC MS: ES+ 594.5.

Compound 52

Yellow solid, 140.0 mg, 63.80% yield, 99.06% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.36 (d, J=7.84 Hz, 1H), 8.08 (d, J=6.48 Hz,1H), 7.85-7.82 (m, 1H), 7.58 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d, J=6.96Hz, 1H), 5.44-5.42 (m, 1H), 4.35-4.27 (m, 3H), 4.18 (s, 2H), 2.96-2.90(m, 3H), 2.77-2.73 (m, 1H), 2.67-2.62 (m, 1H), 2.10-2.07 (m, 1H),2.00-1.96 (m, 2H), 1.76-1.74 (m, 2H), 1.28-1.19 (m, 4H); LC MS: ES+580.2.

Compound 53

Yellow solid, 255.0 mg, 45.02% yield, 99.45% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.83 (t, J=7.6 Hz, 1H), 7.60 (s, 1H), 7.35 (d, J=7.28 Hz, 1H), 7.31(s, 1H), 7.07 (d, J=7.2 Hz, 1H), 5.44-5.42 (m, 1H), 4.40-4.39 (m, 1H),4.32-4.29 (m, 1H), 4.18 (s, 2H), 3.58-3.57 (m, 1H), 3.05-2.91 (m, 2H),2.76-2.72 (m, 1H), 2.66-2.63 (m, 2H), 2.40-2.33 (m, 2H), 2.09-2.08 (m,1H), 1.94-1.87 (m, 3H), 1.78-1.59 (m, 5H), 1.33 (s, 3H); LC MS: ES+540.5.

Compound 54

Yellow solid, 45.0 mg, 35.77% yield, 95% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.09 (s, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.84 Hz,1H), 7.83 (t, J=7.54 Hz, 1H), 7.60 (s, 1H), 7.35 (d, J=7.28 Hz, 1H),7.32 (s, 1H), 7.07 (d, J=7.16 Hz, 1H), 5.43-5.40 (m, 1H), 4.33-4.31 (m,2H), 4.18 (s, 5H), 3.98 (s, 4H), 3.34-3.31 (m, 1H), 3.20-3.14 (m, 1H),2.98-2.91 (m, 1H), 2.75-2.63 (m, 3H), 2.10-2.07 (m, 1H), 2.01-1.92 (m,2H), 1.83-1.80 (m, 1H), 1.67-1.64 (m, 1H); LC MS: ES+ 574.2.

Example 32. General Synthesis of Compound 55-Compound 66

To a stirred solution of Amine (1.0 equiv) in THF (6 mL/mmol) was addedTriethylamine (2.0 equiv) at 0° C. Then Aldehyde (1.0 equiv),Phenylsilane (1.0 equiv) and Dibutyltindichloride (1.2 equiv) were addedto the reaction mixture. The resulting solution was stirred at 90° C.for 16 hours. Reaction mixture was then diluted with Ethyl acetate andwashed with aqueous NaHCO₃ solution, water (×3) and brine. The organiclayer was then dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. Crude mass was then purified by CombiFlash ISCOcolumn, eluting with 3% methanol in DCM to afford the final compound.

Compound 55

Yellow solid, 3.8 g, 71.92% yield, 99.49% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.82 (t, J=7.6 Hz, 1H), 7.57 (s, 1H), 7.35 (d, J=7.24 Hz, 1H), 7.28(s, 1H), 7.06 (d, J=7.24 Hz, 1H), 5.43 (dd, J=12.64, 4.8 Hz, 1H), 4.17(s, 2H), 3.99-3.96 (m, 1H), 2.94-2.90 (m, 1H), 2.75-2.62 (m, 4H), 2.22(s, 2H), 2.09-2.02 (m, 3H), 1.99-1.69 (m, 8H), 1.61-1.56 (m, 2H), 1.13(s, 3H); LC MS: ES+ 526.4.

Compound 56

Yellow solid, 95 mg, 40.71% yield, 96.71% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.37 (d, J=8.04 Hz, 1H), 8.08 (d, J=6.84 Hz,1H), 7.82 (t, J=7.44 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J=7.12 Hz, 1H),7.28 (s, 1H), 7.06 (d, J=7.24 Hz, 1H), 5.44-5.42 (m, 1H), 4.17 (s, 2H),3.98-3.97 (m, 1H), 3.05 (s, 3H), 2.98-2.91 (m, 3H), 2.79-2.72 (m, 1H),2.66-2.62 (m, 1H), 2.46 (s, 2H), 2.19-2.07 (m, 3H), 1.98-1.93 (m, 2H),1.85-1.83 (m, 6H), 1.66-1.64 (m, 1H), 1.55-1.50 (m, 1H); LC MS: ES+542.3.

Compound 57

Yellow solid, 179.0 mg, 58.52% yield, 98.70% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.88 Hz,1H), 7.83 (t, J=7.62 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J=7.32 Hz, 1H),7.29 (s, 1H), 7.07 (d, J=7.24 Hz, 1H), 5.43 (dd, J=12.2, 4.72 Hz, 1H),4.17 (s, 2H), 4.03-4.00 (m, 1H), 2.95-2.91 (m, 1H), 2.84-2.81 (m, 2H),2.77-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.56 (s, 2H), 2.28-2.21 (m, 2H),2.19-2.01 (m, 5H), 1.93-1.86 (m, 6H); LC MS: ES+ 580.5.

Compound 58

Yellow solid, 75.0 mg, 54.65% yield, 96.49% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.6 Hz,1H), 7.83 (t, J=7.72 Hz, 1H), 7.57 (s, 1H), 7.35 (d, J=7.24 Hz, 1H),7.28 (s, 1H), 7.07 (d, J=7.16 Hz, 1H), 5.45-5.42 (m, 1H), 4.17 (s, 2H),3.98-3.97 (m, 1H), 3.07 (s, 3H), 2.96-2.94 (m, 3H), 2.76-2.62 (m, 2H),2.26 (s, 2H), 2.18-2.15 (m, 2H), 2.09-2.08 (m, 1H), 1.86-1.83 (m, 4H),1.07 (s, 6H); LC MS: ES+ 530.3.

Compound 59

Yellow solid, 20.0 mg, 14.35% yield, 95.02% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.92 Hz,1H), 7.83 (t, J=7.62 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J=7.32 Hz, 1H),7.29 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 4.17 (s, 2H), 4.01-3.98 (m, 1H),2.98-2.91 (m, 3H), 2.77-2.72 (m, 1H), 2.67-2.62 (m, 2H), 2.55-2.50 (m,2H), 2.19-2.04 (m, 6H), 1.88-1.84 (m, 4H), 1.73-1.71 (m, 1H), 1.47-1.45(m, 1H); LC MS: ES+ 530.2.

Compound 60

Yellow solid, 30 mg, 20.51% yield, 99.39% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.83 (t, J=7.62 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.32 Hz, 1H),7.29 (s, 1H), 7.07 (d, J=7.32 Hz, 1H), 5.43 (dd, J=12.52, 4.64 Hz, 1H),4.17 (s, 2H), 4.04-4.00 (m, 1H), 2.96-2.89 (m, 3H), 2.77-2.72 (m, 1H),2.65-2.62 (m, 3H), 2.38-2.32 (m, 2H), 2.27-2.20 (m, 2H), 2.18-2.05 (m,4H), 1.98-1.96 (m, 1H), 1.87-1.85 (m, 4H); LC MS: ES+ 537.6.

Compound 61

Yellow solid, 15.0 mg, 5.19% yield, 94.51% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.83 (t, J=7.6 Hz, 1H), 7.58 (s, 1H), 7.36 (d, J=7.36 Hz, 1H), 7.30(s, 1H), 7.07 (d, J=7.24 Hz, 1H), 5.43 (dd, J=13.04, 5.28 Hz, 1H), 4.18(s, 2H), 4.03-4.01 (m, 1H), 2.96-2.93 (m, 3H), 2.77-2.62 (m, 2H), 2.45(s, 2H), 2.42-2.32 (m, 2H), 2.09-2.06 (m, 1H), 1.90-1.85 (m, 4H), 1.25(s, 6H); LC MS: ES+ 525.5.

Compound 62

Yellow solid, 120.0 mg, 60.46% yield, 95% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.08 Hz, 1H), 8.08 (d, J=6.0 Hz,1H), 7.85-7.83 (m, 1H), 7.58 (s, 1H), 7.35 (d, J=7.0 Hz, 1H), 7.29 (s,1H), 7.07 (d, J=6.52 Hz, 1H), 5.44-5.42 (m, 1H), 4.17 (s, 2H), 4.02-4.01(m, 1H), 2.95-2.93 (m, 3H), 2.76-2.72 (m, 1H), 2.66-2.62 (m, 1H),2.06-1.99 (m, 3H), 1.88-1.86 (m, 4H), 0.94 (s, 2H), 0.70 (s, 2H); LC MS:ES+ 566.4.

Compound 63

Yellow solid, 75.0 mg, 42.55% yield, 97.14% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.38 (d, J=8.32 Hz, 1H), 8.08 (d, J=6.76 Hz,1H), 7.83 (t, J=7.54 Hz, 1H), 7.57 (s, 1H), 7.36 (d, J=7.64 Hz, 1H),7.29 (s, 1H), 7.07 (d, J=7.24 Hz, 1H), 5.44-5.42 (m, 1H), 4.17 (s, 2H),3.99-3.97 (m, 1H), 2.99-2.91 (m, 1H), 2.81-2.77 (m, 2H), 2.67-2.62 (m,1H), 2.33-2.27 (m, 2H), 2.05-2.04 (m, 3H), 1.89-1.83 (m, 4H), 1.60-1.58(m, 1H), 0.83 (s, 9H); LC MS: ES+ 514.7.

Compound 64

Yellow solid, 119.0 mg, 43.26% yield, 96.88% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.16 Hz, 1H), 8.08 (d, J=6.88 Hz,1H), 7.83 (t, J=7.64 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J=7.24 Hz, 1H),7.29 (s, 1H), 7.07 (d, J=7.24 Hz, 1H), 5.44-5.42 (m, 1H), 4.18 (s, 2H),4.00-3.99 (m, 1H), 3.00-2.91 (m, 3H), 2.80-2.73 (m, 1H), 2.67-2.62 (m,1H), 2.11-2.10 (m, 3H), 1.91-1.88 (m, 6H), 1.01 (s, 3H), 0.26-0.21 (m,4H); LC MS: ES+ 512.3.

Compound 65

Yellow solid, 100.0 mg, 59.76% yield, 96.30% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.83 (t, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.32 Hz, 1H), 7.30(s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.6, 5.0 Hz, 1H), 4.18(s, 2H), 4.03-4.01 (m, 1H), 3.12-2.90 (m, 3H), 2.80-2.62 (m, 4H),2.22-2.19 (m, 2H), 2.09-2.07 (m, 1H), 1.90-1.88 (m, 4H), 0.99-0.95 (m,2H), 0.66-0.65 (m, 2H); LC MS: ES+ 516.3.

Compound 66

Yellow solid, 50 mg, 29.55% yield, 97.44% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.92 Hz,1H), 7.83 (t, J=7.66 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.28 Hz, 1H),7.29 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.64, 4.88 Hz, 1H),4.18 (s, 2H), 4.01-3.99 (m, 1H), 3.20 (s, 3H), 3.13-3.05 (m, 2H),3.03-2.90 (m, 1H), 2.80-2.62 (m, 2H), 2.50-2.48 (m, 2H), 2.10-2.07 (m,3H), 1.88-1.85 (m, 4H), 0.67 (s, 2H), 0.42 (s, 2H); LC MS: ES+ 528.2.

Example 33. Synthesisof-3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 67) and3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 68)

Step 1: Synthesis of3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneand3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:Racemic 300 mg of3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dionewas separated to its enantiomers by Reverse phase prep HPLC to afford3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 67 (100.0 mg, 33% yield, eluted as first fraction, % ee 99) and3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 68 (85.0 mg, 28% yield, eluted as second fraction, % ee 99) asyellow solids. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d,J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.60(s, 1H), 7.35 (d, J=7.28 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.2 Hz, 1H),5.44-5.42 (m, 1H), 4.40-4.39 (m, 1H), 4.32-4.29 (m, 1H), 4.18 (s, 2H),3.58-3.57 (m, 1H), 3.05-2.91 (m, 2H), 2.76-2.72 (m, 1H), 2.66-2.63 (m,2H), 2.40-2.33 (m, 2H), 2.09-2.08 (m, 1H), 1.94-1.87 (m, 3H), 1.78-1.59(m, 5H), 1.33 (s, 3H); LC MS: ES+ 540.5.

Example 34. Synthesis of3-(6-((1-(4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dionehydrochloride (Compound 69)

Step 1: Synthesis of 1-benzyl-1-bromo-4-methyl-pyridinium bromide (2):To the stirred solution of 4-methylpyridine (20 g, 214.76 mmol, 20.90mL) in dry grade acetonitrile (100 mL), Benzyl bromide (44.08 g, 257.71mmol, 30.61 mL) was added at rt and the resultant reaction mixture washeated at 100° C. for 12 hr. After completion of reaction (monitored byTLC), volatiles were removed under vacuum and the solid thus obtainedwas triturated with ethyl acetate and ether to obtain1-benzyl-1-bromo-4-methyl-pyridine (2) (56 g, 211.99 mmol, 98.71% yield)as yellowish solid. LC MS: ES+ 183.9.

Step 2: Synthesis of 1-benzyl-4-methyl-3,6-dihydro-2H-pyridine (3): Tothe stirred solution of 1-benzyl-1-bromo-4-methyl-pyridinium bromide (2)(56.0 g, 211.99 mmol) in mixed solvent of EtOH (72 mL) and Water (8 mL),Sodium borohydride (20.05 g, 529.98 mmol, 18.74 mL) was added portionwise at 0° C. After complete addition, reaction mass was stirred for 12hr at ambient temperature. After completion of the reaction as monitoredby LC MS, the reaction mixture was quenched with addition of water (30mL) and ethanol was removed under reduced pressure. The aqueous part wasextracted with ethyl acetate (2×200 ml). The combine organic part wasdried over anhydrous Na₂SO₄ and concentrated under vacuum. The cruderesidue was purified by column chromatography (100-200 silica; 2% EtOAcin Hexane) to afford 1-benzyl-4-methyl-3,6-dihydro-2H-pyridine (3) (39.3g, 209.85 mmol, 98.99% yield) yellow oil, LC MS: ES+ 187.8.

Step 3: Synthesis of tert-butylN-(1-benzyl-4-methyl-4-piperidyl)-N-(tert-butoxycarbonylamino) carbamate(4): To a well degassed stirred solution of1-benzyl-4-methyl-3,6-dihydro-2H-pyridine (3) (25.0 g, 133.49 mmol) in2-propanol (20 mL), phenylsilane (14.44 g, 133.49 mmol, 16.45 mL) and[(Z)-1-tert-butyl-3-hydroxy-4,4-dimethyl-pent-2-enylidene]oxonium;manganese (1.61 g, 2.67 mmol) was added at 0° C. followed bytert-butyl-N-tert-butoxycarbonyliminocarbamate (46.11 g, 200.23 mmol)under nitrogen atmosphere. After complete addition, reaction mixture wasstirred at same temperature for 6 hr. After completion of the reaction(monitored by TLC), reaction mass was evaporated and the crude thusobtained was purified by column chromatography (100-200 silica; 30%EtOAc in Hexane) to afford tert-butylN-(1-benzyl-4-methyl-4-piperidyl)-N-(tert-butoxycarbonylamino)carbamate(4) (15 g, 35.75 mmol, 26.78% yield) as yellow sticky solid, LC MS: ES+420.0.

Step 4: Synthesis of (1-benzyl-4-methyl-4-piperidyl)hydrazine (5): 4MDioxane-HCl (30 mL) was added to tert-butylN-(1-benzyl-4-methyl-4-piperidyl)-N-(tert-butoxycarbonylamino)carbamate(4) (15.0 g, 35.75 mmol), at 0° C. and stirred for 8 hr at rt. Aftercompletion of reaction as evidenced from LCMS, volatiles were removedunder vacuum. The crude thus obtained was dissolved in 10% MeOH in DCMand neutralized with Amberlyst-A21 resin. The solid polymer was filteredoff and washed with 10% MeOH in DCM several times. The combined filtratewas concentrated under reduced pressure to afford(1-benzyl-4-methyl-4-piperidyl)hydrazine (5) (7.4 g, 33.74 mmol, 94.37%yield, 90% purity) as yellow solid, LC MS: ES+ 220.0.

Step 5: Synthesis of ethyl1-(1-benzyl-4-methyl-4-piperidyl)pyrazole-4-carboxylate (7): To astirred solution of ethyl 2-formyl-3-oxo-propanoate (6) (4.73 g, 32.83mmol) intoluene (15 mL) crude (1-benzyl-4-methyl-4-piperidyl)hydrazine(5) (6.0 g, 27.36 mmol) was added at 0° C. and heated for 12 hr at 90°C. After completion of the reaction (monitored by LC MS) all thevolatiles were evaporated and crude thus obtained was purified by columnchromatography (100-200 Silica; 30% EtOAc in Hexane as eluent) to affordethyl 1-(1-benzyl-4-methyl-4-piperidyl)pyrazole-4-carboxylate (7) (4.36g, 13.33 mmol, 48.72% yield) as light yellow gum, LC MS: ES+ 328.3.

Step 6: Synthesis of tert-butyl4-(4-ethoxycarbonylpyrazol-1-yl)-4-methyl-piperidine-1-carboxylate (8):To the stirred solution of ethyl1-(1-benzyl-4-methyl-4-piperidyl)pyrazole-4-carboxylate (7) (6.0 g,18.33 mmol) in EtOH (20 mL), tert-butoxycarbonyl tert-butyl carbonate(10.85 g, 49.73 mmol, 11.41 mL) and Triethylamine (7.55 g, 74.59 mmol,10.40 mL) was added. Then the reaction mixture was degassed with Argonfor 15 minutes followed by the addition of 20% Palladium on Carbon(moist) (2.93 g, 27.49 mmol) and the resultant reaction mixture wasstirred under hydrogen atmosphere for 16 hr at RT. After completion ofthe reaction (monitored by TLC and LCMS), the reaction mixture wasfiltered through celite. The filtrate was then concentrated and purifiedby column chromatography (100-200 Silica; 2% Methanol in DCM) to affordthe desired compound tert-butyl4-(4-ethoxycarbonylpyrazol-1-yl)-4-methyl-piperidine-1-carboxylate (8)(4.8 g, 14.23 mmol, 57.22% yield, 99% purity) as brown gum, LC MS: ES+338.3.

Step 7: Synthesis of tert-butyl4-[4-(hydroxymethyl)pyrazol-1-yl]-4-methyl-piperidine-1-carboxylate (9):To the stirred solution of tert-butyl4-(4-ethoxycarbonylpyrazol-1-yl)-4-methyl-piperidine-1-carboxylate (8)(4.8 g, 10.67 mmol) in THF (50 mL), Diisobutylaluminum hydride (10.12 g,71.13 mmol, 60 mL) was added drop wise at −78° C. and stirred for 1 hrat rt under N₂ atmosphere. After complete consumption, as evidenced fromTLC, reaction mass was diluted with ethyl acetate (300 mL) and quenchedwith water (50 mL). Organic phase was separated, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford tert-butyl4-[4-(hydroxymethyl)pyrazol-1-yl]-4-methyl-piperidine-1-carboxylate (9)(4.05 g, 13.72 mmol, 96.43% yield) as brown gum which was carriedforward to the next step without any further purification, LC MS: ES+296.2.

Step 8: Synthesis of tert-butyl4-(4-formylpyrazol-1-yl)-4-methyl-piperidine-1-carboxylate (10): To astirred solution of tert-butyl4-[4-(hydroxymethyl)pyrazol-1-yl]-4-methyl-piperidine-1-carboxylate (9)(4.0 g, 13.54 mmol) in Acetonitrile (20 mL), was added activated MnO₂(9.42 g, 108.34 mmol) and stirred at RT for 24 hr. After completion ofthe reaction (monitored by TLC and LC MS), reaction mass was filteredthrough celite and the filtrate was concentrated under reduced pressure.Crude mass was purified by column chromatography (100-200 silica; 2-3%MeOH in DCM as eluent) to afford tert-butyl4-(4-formylpyrazol-1-yl)-4-methyl-piperidine-1-carboxylate (10) (3.0 g,10.23 mmol, 75.52% yield) as colorless sticky soli. LC MS: ES+ 294.3.

Step 9: Synthesis of tert-butyl4-(4-(hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carboxylate:To the stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 11 (4.3 g,17.33 mmol) in THF (50.0 mL) was added Phenyllithium, typically 1.9M indi-n-butyl ether (1.8 M, 9.63 mL) at −78° C. and the reaction mixturewas stirred at the same temperature for 1 hour followed by the additionof Butyllithium (1.9 M, 10.04 mL) at −78° C. and after the addition wascomplete the temperature was allowed to increase to −40° C. and thereaction mixture was stirred at the same temperature for 30 minutesfollowed by the addition of tert-butyl4-(4-formylpyrazol-1-yl)-4-methyl-piperidine-1-carboxylate 10 (5.08 g,17.33 mmol) in THF (50.0 mL) at −78° C. and then the reaction mixturewas allowed to warm to room temperature and was continued for 16 hours.Reaction mixture was quenched with ammonium chloride solution, dilutedwith ethyl acetate, washed with water and the organic fraction wasseparated. It was then dried over anhydrous sodium sulphate andevaporated under reduced pressure to obtain the crude compound which waspurified by flash chromatography using 0-5% MeOH-DCM to affordtert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methyl-piperidine-1-carboxylate12 (1.5 g, 2.26 mmol, 13.02% yield, 69.6% purity) as brown solid. LC MS:ES+ 462.9.

Step 10: Synthesis of 2,2,2-trifluoroacetaldehyde compound with6-((1-(4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one(1:1): To the stirred solution of tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methyl-piperidine-1-carboxylate12 (1.43 g, 3.09 mmol) in DCE (6 mL) was added Triethylsilane (1.44 g,12.37 mmol, 1.98 mL), Trifluoroacetic acid (2.82 g, 24.73 mmol, 1.91 mL)and the reaction mixture was heated at 80° C. for 2 hours in a sealedtube. The solvent in the reaction mixture was evaporated under reducedpressure and triturated with ether to obtain[4-methyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-piperidyl]2,2,2-trifluoroacetate13 (1.5 g, 1.92 mmol, 62.24% yield, 73.7% purity) as crude which wasused directly in the next step. LC MS: ES+ 347.2.

Step 11: Synthesis of tert-butyl4-methyl-4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:To a stirred solution of[4-methyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-piperidyl]2,2,2-trifluoroacetate13 (1.4 g, 3.04 mmol) in DCM (10.0 mL) was added Triethylamine (923.01mg, 9.12 mmol, 1.27 mL) at 0° C. followed by the addition ofDi-tert-butyl dicarbonate (995.39 mg, 4.56 mmol, 1.05 mL) and thereaction was stirred at room temperature for 16 hours. The reactionmixture was diluted with ethyl acetate, washed with water and theorganic fraction was separated. It was dried over anhydrous sodiumsulphate and evaporated under reduced pressure to obtain the crudecompound which was purified by flash chromatography using 0-5% MeOH-DCMto afford tert-butyl4-methyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate14 (800.0 mg, 1.67 mmol, 54.80% yield, 93% purity) as brown solid. LCMS: ES+ 447.3.

Step 12: Synthesis of tert-butyl4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carboxylate:To the stirred solution of tert-butyl4-methyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate14 (800.0 mg, 1.79 mmol) in THF (20 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (686.46 mg, 17.92 mmol, 60%purity) at cold condition and the reaction mixture was stirred at roomtemperature for 10 minutes followed by the addition of3-bromopiperidine-2,6-dione 15 (1.72 g, 8.96 mmol) portion wise. It wasthen stirred at room temperature for 10 minutes and heated at 70° C. for30 minutes. The reaction mixture was then diluted with ethyl acetate,washed with cold water and the organic fraction was separated. It wasthen dried over anhydrous sodium sulphate and evaporated under reducedpressure to obtain the crude which was washed with ether and pentane toafford tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-methyl-piperidine-1-carboxylate16 (780.0 mg, 1.39 mmol, 77.76% yield, 99.6% purity) as yellow solid. LCMS: ES+ 558.0.

Step 13: Synthesis of3-(6-((1-(4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dionehydrochloride: To the stirred solution of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-methyl-piperidine-1-carboxylate16 (780.0 mg, 1.40 mmol) in Dioxane (5 mL) was added Hydrochloric acidin dioxane (1.40 mmol, 10 mL) and the reaction mixture was stirred atroom temperature for 2 hours. Solvent in the reaction mixture wasevaporated under reduced pressure to obtain a yellow solid which waswashed with ether and pentane to afford3-[6-[[1-(1-chloro-4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 69 (690.0 mg, 1.21 mmol, 86.30% yield, 92.8% purity) as yellowsolid. LC MS: ES+ 458.3.

Example 35. General Synthesis of Compound 70-Compound 93

To an equi-molar mixture of Amine and Acid DMF (6 mL/mmol) were addedHATU (1.5 equiv) and DIPEA (5.0 equiv) at 0° C. The resulting solutionwas stirred at ambient temperature for 16 hours. The reaction mixturewas then diluted with Ethyl acetate and washed with aqueous NaHCO₃solution, water (×3) and brine. The organic layer was then dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. Crude mass wasthen purified by CombiFlash ISCO column, eluting with 2% methanol in DCMto afford 3.

Compound 70

Yellow solid, 30.0 mg, 63.04% yield, 100% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.04 Hz, 1H), 8.08 (d, J=7.0 Hz,1H), 7.85-7.81 (m, 2H), 7.36-7.33 (m, 2H), 7.07 (d, J=7.2 Hz, 1H),5.45-5.42 (m, 1H), 4.20 (s, 2H), 4.15 (s, 3H), 3.96 (s, 4H), 3.74-3.70(m, 1H), 3.22-3.18 (m, 1H), 3.05-2.91 (m, 3H), 2.77-2.72 (m, 1H),2.67-2.62 (m, 1H), 2.41-2.27 (m, 2H), 2.08-2.07 (m, 1H), 1.83-1.82 (m,1H), 1.72-1.71 (m, 1H), 1.34 (s, 3H); LC MS: ES+ 588.5.

Compound 71

Yellow solid 40.0 mg, 57.30% yield, 98.76% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.92 Hz,1H), 7.83 (t, J=7.64 Hz, 1H), 7.78 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d,J=7.32 Hz, 1H), 5.43 (dd, J=12.8, 5.2 Hz, 1H), 4.39 (s, 1H), 4.20 (s,2H), 3.75-3.71 (m, 1H), 3.64 (s, 2H), 3.43-3.41 (m, 1H), 3.14-3.12 (m,2H), 2.95-2.90 (m, 1H), 2.77-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.33-2.29(m, 2H), 2.09-2.02 (m, 3H), 1.77-1.70 (m, 4H), 1.35 (s, 3H); LC MS: ES+568.5.

Compound 72

Yellow solid, 35 mg, 47.95% yield, 98.63% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.39 (d, J=8.28 Hz, 1H), 8.08 (d, J=7.0 Hz,1H), 7.85-7.80 (m, 2H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.2 Hz, 1H), 5.43(dd, J=12.8, 5.2 Hz, 1H), 4.21 (s, 2H), 3.80-3.78 (m, 2H), 2.95-2.88 (m,2H), 2.76-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.36-2.34 (m, 2H), 2.09-2.07(m, 1H), 2.02-1.98 (m, 2H), 1.82-1.80 (m, 2H), 1.76-1.62 (m, 5H),1.54-1.50 (m, 2H), 1.38 (s, 3H), 1.24-1.18 (m, 2H); LC MS: ES+ 593.3.

Compound 73

Yellow solid, 20 mg, 22.55% yield, 95% purity. ¹H NMR (400 MHz, DMSO-d6)δ 11.11 (s, 1H), 8.39 (d, J=8.08 Hz, 1H), 8.08 (d, J=6.56 Hz, 1H), 7.83(t, J=7.48 Hz, 1H), 7.76 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d, J=7.48 Hz,1H), 5.45-5.42 (m, 1H), 4.20 (s, 2H), 3.76-3.74 (m, 2H), 3.54-3.52 (m,1H), 3.27-3.25 (m, 2H), 3.14-3.01 (m, 2H), 2.86-2.84 (m, 5H), 2.32-2.25(m, 2H), 2.10-2.07 (m, 2H), 1.77-1.75 (m, 7H), 1.36 (s, 3H); LC MS: ES+595.3.

Compound 74

Yellow solid, 21 mg, 29.72% yield, 99.82% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.6 Hz, 1H), 8.08 (d, J=7.2 Hz,1H), 7.83 (t, J=7.66 Hz, 1H), 7.78 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d,J=6.64 Hz, 1H), 5.45-5.42 (m, 1H), 4.21 (s, 2H), 3.70-3.69 (m, 2H),3.31-3.24 (m, 3H), 3.11-3.09 (m, 2H), 2.96-2.92 (m, 1H), 2.85-2.84 (m,4H), 2.77-2.73 (m, 1H), 2.67-2.62 (m, 1H), 2.33-2.26 (m, 2H), 2.09-2.08(m, 1H), 1.85-1.83 (m, 3H), 1.75-1.74 (m, 2H), 1.36 (s, 3H); LC MS: ES+581.6.

Compound 75

Yellow solid, 60.0 mg, 70.33% yield, 99.57% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.09 (s, 1H), 8.36 (d, J=8.24 Hz, 1H), 8.06 (d, J=6.92 Hz,1H), 7.80 (t, J=7.56 Hz, 1H), 7.76 (s, 1H), 7.33-7.31 (m, 2H), 7.05 (d,J=7.36 Hz, 1H), 5.44-5.39 (m, 1H), 4.18 (s, 2H), 3.68-3.64 (m, 1H),3.47-3.45 (m, 1H), 3.17-3.12 (m, 1H), 3.07-3.02 (m, 1H), 2.94-2.89 (m,1H), 2.74-2.70 (m, 1H), 2.65-2.59 (m, 1H), 2.31-2.29 (m, 1H), 2.23-2.20(m, 1H), 2.07-2.05 (m, 1H), 1.94 (s, 3H), 1.79-1.73 (m, 1H), 1.69-1.63(m, 1H), 1.32 (s, 3H); LC MS: ES+ 500.2.

Compound 76

Yellow solid, 13 mg, 30.28% yield, 95% purity. ¹H NMR (400 MHz, DMSO-d6)δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H),7.85-7.80 (m, 2H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.28 Hz, 1H), 6.04-5.76(m, 1H), 5.43 (dd, J=12.68, 5.0 Hz, 1H), 4.21 (s, 2H), 3.78-3.73 (m,2H), 3.21-3.19 (m, 2H), 2.95-2.90 (m, 1H), 2.77-2.72 (m, 1H), 2.66-2.62(m, 1H), 2.34-2.32 (m, 2H), 2.09-2.07 (m, 1H), 1.77-1.76 (m, 2H), 1.34(s, 3H), 1.05-0.99 (m, 4H); LC MS: ES+ 576.5.

Compound 77

Yellow solid, 110.0 mg, 50.62% yield, 99.54% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.82 (m, 2H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd,J=12.72, 5.08 Hz, 1H), 4.21 (s, 2H), 3.79-3.75 (m, 2H), 3.29-3.22 (m,2H), 2.96-2.88 (m, 1H), 2.77-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.36-2.32(m, 2H), 2.09-2.07 (m, 1H), 1.79-1.78 (m, 2H), 1.35 (s, 3H), 1.28-1.26(m, 2H), 1.22-1.17 (m, 2H); LC MS: ES+ 594.3.

Compound 78

Yellow solid, 110.0 mg, 49.02% yield, 98.67% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.28 Hz, 1H), 8.08 (d, J=7.0 Hz,1H), 7.82 (t, J=7.68 Hz, 1H), 7.79 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d,J=7.32 Hz, 1H), 5.43 (dd, J=12.72, 5.08 Hz, 1H), 4.21 (s, 2H), 3.79-3.78(m, 1H), 3.13-3.06 (m, 2H), 2.95-2.88 (m, 1H), 2.77-2.72 (m, 1H),2.69-2.61 (m, 4H), 2.41-2.39 (m, 2H), 2.33-2.31 (m, 2H), 2.10-2.07 (m,1H), 1.94-1.91 (m, 1H), 1.77-1.76 (m, 3H), 1.35 (s, 3H); LC MS: ES+608.3.

Compound 79

Yellow solid, 122.0 mg, 53.98% yield, 98.63% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.92 Hz,1H), 7.86-7.82 (m, 2H), 7.36-7.31 (m, 2H), 7.07 (d, J=7.24 Hz, 1H),5.45-5.42 (m, 1H), 4.21 (s, 2H), 3.81-3.80 (m, 2H), 3.19-3.18 (m, 1H),2.97-2.88 (m, 1H), 2.80-2.62 (m, 2H), 2.39-2.38 (m, 2H), 2.08-2.07 (m,2H), 1.85-1.84 (m, 2H), 1.56-1.47 (m, 4H), 1.37 (s, 3H); LC MS: ES+551.2.

Compound 80

Yellow solid, 125.0 mg, 61.62% yield, 99.27% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.6 Hz,1H), 7.85-7.82 (m, 2H), 7.36-7.35 (m, 2H), 7.07 (d, J=6.96 Hz, 1H),5.45-5.42 (m, 1H), 4.21 (s, 2H), 3.81-3.80 (m, 2H), 3.24-3.23 (m, 2H),2.98-2.91 (m, 1H), 2.80-2.57 (m, 2H), 2.38-2.37 (m, 2H), 2.08-2.07 (m,1H), 1.83-1.82 (m, 2H), 1.50 (s, 6H), 1.38 (s, 3H); LC MS: ES+ 553.5.

Compound 81

Yellow solid, 110.0 mg, 51.39% yield, 99.37% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.28 Hz, 1H), 7.82 (t, J=7.5 Hz,1H), 7.77 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d, J=6.72 Hz, 1H), 5.45-5.42(m, 1H), 4.20 (s, 2H), 3.70-3.69 (m, 2H), 3.59-3.57 (m, 2H), 3.46-3.38(m, 2H), 3.27-3.23 (m, 2H), 2.98-2.90 (m, 1H), 2.80-2.72 (m, 1H),2.67-2.62 (m, 1H), 2.29-2.26 (m, 2H), 2.08-2.07 (m, 1H), 2.00-1.87 (m,2H), 1.76-1.72 (m, 2H), 1.42-1.39 (m, 2H), 1.35 (s, 3H), 1.21 (s, 3H);LC MS: ES+ 584.3.

Compound 82

Yellow solid, 35.0 mg, 40.38% yield, 97.37% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.08 (br s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96Hz, 1H), 7.83 (t, J=7.64 Hz, 1H), 7.78 (s, 1H), 7.36-7.34 (m, 2H), 7.07(d, J=7.32 Hz, 1H), 5.43 (dd, J=12.76, 5.2 Hz, 1H), 4.21 (s, 2H),3.76-3.72 (m, 2H), 3.23-3.18 (m, 2H), 2.96-2.91 (m, 1H), 2.77-2.72 (m,1H), 2.67-2.62 (m, 1H), 2.33-2.30 (m, 2H), 2.09-2.07 (m, 1H), 1.81-1.75(m, 2H), 1.44 (s, 6H), 1.36 (s, 3H); LC MS: ES+ 596.2.

Compound 83

Yellow solid, 30.0 mg, 38.31% yield, 97.66% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.83 (t, J=7.66 Hz, 1H), 7.79 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d,J=7.32 Hz, 1H), 5.43 (dd, J=12.8, 5.12 Hz, 1H), 4.21 (s, 2H), 3.74-3.70(m, 2H), 3.23-3.21 (m, 2H), 2.95-2.90 (m, 1H), 2.77-2.72 (m, 1H),2.67-2.62 (m, 1H), 2.32-2.28 (m, 2H), 2.09-2.07 (m, 1H), 1.78-1.73 (m,2H), 1.35 (s, 3H), 1.18 (s, 3H), 0.77-0.75 (m, 2H), 0.51-0.49 (m, 2H);LC MS: ES+ 540.3.

Compound 84

Yellow solid, 26.0 mg, 32.18% yield, 97.80% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.09 (s, 1H), 8.39 (d, J=8.12 Hz, 1H), 8.08 (d, J=6.92 Hz,1H), 7.85-7.80 (m, 2H), 7.37-7.34 (m, 2H), 7.07 (d, J=7.12 Hz, 1H),5.45-5.42 (m, 1H), 4.21 (s, 2H), 4.08-4.07 (m, 1H), 3.74-3.73 (m, 1H),3.55-3.54 (m, 1H), 3.20-3.15 (m, 1H), 3.10 (s, 3H), 2.98-2.91 (m, 1H),2.76-2.72 (m, 1H), 2.67-2.56 (m, 1H), 2.34-2.32 (m, 2H), 2.09-2.08 (m,1H), 1.78-1.77 (m, 2H), 1.36 (s, 3H), 1.29 (s, 6H); LC MS: ES+ 558.3.

Compound 85

Yellow solid, 32.0 mg, 39.17% yield, 99.17% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.92 Hz,1H), 7.82 (t, J=7.64 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d,J=7.36 Hz, 1H), 5.45-5.42 (m, 1H), 4.20 (s, 2H), 3.72-3.67 (m, 2H),3.33-3.29 (m, 3H), 3.22-3.18 (m, 4H), 2.96-2.94 (m, 1H), 2.80-2.72 (m,1H), 2.66-2.62 (m, 1H), 2.29-2.25 (m, 2H), 2.09-2.07 (m, 1H), 1.74-1.69(m, 2H), 1.35 (s, 3H), 1.15 (s, 6H); LC MS: ES+ 572.3.

Compound 86

Yellow solid, 125.0 mg, 42.73% yield, 97.69% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=7.0 Hz,1H), 7.85-7.80 (m, 2H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.28 Hz, 1H), 5.43(dd, J=12.84, 5.2 Hz, 1H), 4.21 (s, 2H), 3.80-3.75 (m, 1H), 3.45-3.42(m, 1H), 3.18-3.14 (m, 2H), 2.96-2.91 (m, 1H), 2.76-2.62 (m, 4H),2.57-2.54 (m, 2H), 2.41-2.32 (m, 2H), 2.11-2.07 (m, 2H), 1.87-1.78 (m,3H); LC MS: ES+ 565.2.

Compound 87

Yellow solid, 165.0 mg, 61.69% yield, 99.45% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.83 (t, J=7.64 Hz, 1H), 7.79 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d,J=7.32 Hz, 1H), 5.43 (dd, J=12.8, 5.12 Hz, 1H), 4.18 (s, 2H), 3.80-3.68(m, 2H), 3.39-3.38 (m, 1H), 3.14-3.12 (m, 1H), 2.99-2.90 (m, 1H),2.80-2.72 (m, 1H), 2.69-2.62 (m, 1H), 2.34-2.32 (m, 1H), 2.25-2.23 (m,1H), 2.09-2.07 (m, 1H), 1.97-1.92 (m, 1H), 1.81-1.67 (m, 2H), 1.36 (s,3H), 0.680-0.66 (m, 4H); LC MS: ES+ 526.2.

Compound 88

Yellow solid, 38.0 mg, 50.97% yield, 97.04% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=7.0 Hz,1H), 7.82 (t, J=7.62 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d,J=7.28 Hz, 1H), 5.43 (dd, J=12.68, 5.08 Hz, 1H), 4.20 (s, 2H), 3.95 (t,J=6.42 Hz, 2H), 3.66-3.65 (m, 1H), 3.46-3.45 (m, 1H), 3.10-3.08 (m, 2H),2.94-2.90 (m, 1H), 2.77-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.33-2.27 (m,2H), 2.10-1.99 (m, 7H), 1.74-1.73 (m, 2H), 1.34 (s, 3H), 1.11 (s, 3H);LC MS: ES+ 596.3.

Compound 89

Yellow solid, 40.0 mg, 54.86% yield, 96.57% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.82 (t, J=7.62 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d,J=7.28 Hz, 1H), 5.43 (dd, J=12.76, 5.16 Hz, 1H), 4.20 (s, 2H), 3.64-3.62(m, 1H), 3.40-3.39 (m, 1H), 3.09-3.07 (m, 2H), 2.99-2.90 (m, 1H),2.81-2.72 (m, 1H), 2.69-2.62 (m, 1H), 2.34-2.26 (m, 2H), 2.09-2.07 (m,4H), 1.79-1.60 (m, 9H), 1.34 (s, 3H); LC MS: ES+ 580.3.

Compound 90

Yellow solid, 40.0 mg, 56.75% yield, 97.82% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.04 Hz, 1H), 8.08 (d, J=7.0 Hz,1H), 7.83 (t, J=7.64 Hz, 1H), 7.78 (s, 1H), 7.35-7.33 (m, 2H), 7.07 (d,J=7.28 Hz, 1H), 5.45-5.42 (m, 1H), 4.20 (s, 2H), 3.75-3.67 (m, 4H),3.14-3.09 (m, 1H), 2.95-2.91 (m, 1H), 2.83-2.79 (m, 1H), 2.76-2.72 (m,1H), 2.67-2.62 (m, 1H), 2.49-2.47 (m, 1H), 2.33-2.29 (m, 2H), 2.08-2.07(m, 1H), 1.98-1.96 (m, 2H), 1.76-1.72 (m, 2H), 1.60-1.57 (m, 2H), 1.35(s, 3H); LC MS: ES+ 568.3.

Compound 91

Yellow solid, 40.0 mg, 58.47% yield, 97.94% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.12 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.83 (t, J=7.64 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d,J=7.2 Hz, 1H), 5.45-5.42 (m, 1H), 4.20 (s, 2H), 3.69-3.63 (m, 2H),3.09-3.06 (m, 1H), 2.98-2.90 (m, 1H), 2.79-2.72 (m, 1H), 2.67-2.62 (m,1H), 2.43 (s, 2H), 2.33-2.22 (m, 2H), 2.06-2.00 (m, 7H), 1.75-1.72 (m,2H), 1.35 (s, 3H); LC MS: ES+ 552.3.

Compound 92

Yellow solid, 110 mg, 48.55% yield, 98.94% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=Hz, 1H), 8.08 (d, J=Hz, 1H), 7.82(t, J=Hz, 1H), 7.78 (s, 1H), 7.36-7.33 (m, 2H), 7.07 (d, J=Hz, 1H), 5.43(dd, J=Hz, 1H), 4.20 (s, 2H), 3.69-3.67 (m, 1H), 3.29-3.28 (m, 1H),3.07-3.05 (m, 2H), 2.99-2.90 (m, 1H), 2.80-2.69 (m, 1H), 2.67-2.62 (m,1H), 2.39-2.28 (m, 4H), 2.09-2.07 (m, 1H), 1.94-1.83 (m, 1H), 1.78-1.74(m, 4H), 1.62-1.55 (m, 1H), 1.34 (s, 3H), 1.31 (s, 3H); LC MS: ES+554.2.

Compound 93

Yellow solid, 120 mg, 43.48% yield, 99.32% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.92 Hz,1H), 7.83 (t, J=7.58 Hz, 1H), 7.78 (s, 1H), 7.35-7.33 (m, 1H), 7.07 (d,J=7.08 Hz, 1H), 5.44-5.42 (m, 1H), 4.21 (s, 2H), 3.70-3.68 (m, 2H),3.25-3.22 (m, 2H), 2.98-2.91 (m, 1H), 2.76-2.72 (m, 1H), 2.67-2.62 (m,1H), 2.27-2.26 (m, 2H), 2.09-2.08 (m, 1H), 1.76-1.71 (m, 2H), 1.35 (s,3H), 1.16 (s, 9H); LC MS: ES+ 542.2.

Example 36. General Synthesis of Compound 94-Compound 98

To an equi-molar mixture of Amine and Acid DMF (2 ml) were added HATU(1.5 equiv) and DIPEA (5.0 equiv) at 0° C. The resulting solution wasstirred at ambient temperature for 16 hours. The reaction mixture wasthen diluted with Ethyl acetate and washed with aqueous NaHCO3 solution,water (×3) and brine. The organic layer was then dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. Crude mass was thenpurified by Combi-Flash (eluting with 2% methanol in DCM) followed byPrep-TLC to afford 3.

Compound 94

Yellow solid 28 mg, 41.41% yield, 99.07% Purity. ¹H NMR (400 MHz,DMSO-d6): δ 11.10 (s, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.09 (d, J=7.0 Hz,1H), 7.85-7.81 (m, 1H), 7.79 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.2Hz, 1H), 5.46-5.41 (m, 1H), 4.78-4.74 (m, 2H), 4.24-4.21 (m, 4H), 3.75(m, 1H), 3.07 (m, 1H), 2.98-2.86 (m, 3H), 2.76-2.62 (m, 2H), 2.32-2.31(m, 2H), 2.09-2.08 (m, 1H), 1.78-1.75 (m, 2H), 1.50 (s, 3H), 1.35 (s,3H). LCMS: (ES+)=556.4 [M+H]+.

Compound 95

Yellow solid 40 mg, 56.44% yield, 98.61% Purity. ¹H NMR (400 MHz,DMSO-d6): δ 11.11 (s, 1H), 8.39 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.0 Hz,1H), 7.85-7.81 (m, 1H), 7.78 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.3Hz, 1H), 5.46-5.41 (m, 1H), 4.42 (m, 1H), 4.29 (m, 1H), 4.21 (m, 2H),3.73-3.69 (m, 1H), 3.24-3.19 (m, 2H), 2.96-2.90 (m, 1H), 2.77-2.73 (m,1H), 2.69-2.63 (m, 2H), 2.32-2.28 (m, 2H), 2.09-2.07 (m, 1H), 1.78-1.73(m, 2H), 1.36 (s, 3H), 1.22-1.21 (m, 6H). LCMS (ES+)=560.3 [M+H]+.

Compound 96

Yellow solid 32 mg, 47% yield, 98.2% Purity. ¹H NMR (400 MHz, DMSO-d6):δ 11.12 (s, 1H), 8.40 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.9 Hz, 1H),7.85-7.81 (m, 2H), 7.34 (m, 2H), 7.08 (d, J=7.2 Hz, 1H), 5.44-5.43 (m,1H), 4.21 (s, 2H), 4.21 (m, 2H), 3.29 (m, 1H), 3.18 (m, 1H), 2.95-2.91(m, 1H), 2.76-2.62 (m, 2H), 2.33 (m, 2H), 2.08 (m, 1H), 1.78 (m, 2H),1.55-1.49 (m, 3H), 1.37 (s, 9H). LCMS (ES+)=546.2 [M+H]+.

Compound 97

Yellow solid 36 mg, 51.71% yield, 98.93% Purity. ¹H NMR (400 MHz,DMSO-d6): δ 11.11 (s, 1H), 8.40 (d, J=8.3 Hz, 1H), 8.08 (d, J=7.0 Hz,1H), 7.85-7.81 (m, 2H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.2 Hz, 1H),5.44-5.42 (m, 1H), 4.20 (s, 2H), 3.86 (m, 2H), 2.98-2.91 (m, 1H),2.79-2.73 (m, 1H), 2.69-2.62 (m, 2H), 2.33 (m, 2H), 2.08 (m, 1H), 1.80(m, 3H), 1.73 (s, 6H), 1.38 (s, 3H). LCMS (ES+)=562.4 [M+H]+.

Compound 98

Yellow solid 15 mg, 18.59% yield, 99.44% Purity. ¹H NMR (400 MHz,DMSO-d6): δ 11.1 (s, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.08 (d, J=7.0 Hz,1H), 7.83 (t, J=7.6 Hz, 1H), 7.78 (s, 1H), 7.36-7.34 (m, 2H), 7.07 (d,J=7.2 Hz, 1H), 5.46-5.42 (m, 1H), 4.52-4.49 (m, 1H), 4.21 (s, 2H),3.73-3.70 (m, 2H), 3.39-3.38 (m, 2H), 3.23-3.18 (m, 2H), 2.95-2.92 (m,1H), 2.76-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.31-2.28 (m, 2H), 2.09-2.06(m, 1H), 1.77-1.72 (m, 2H), 1.35 (s, 3H), 1.13 (s, 6H). LCMS(ES+)=558.6[M+H]+.

Example 37. General Synthesis of Compound 99-Compound 106

To a stirred solution of Amine (1.0 equiv) in THF (6 mL/mmol) was addedTriethylamine (2.0 equiv) at 0° C. Then Aldehyde (1.0 equiv),Phenylsilane (1.0 equiv) and Dibutyltindichloride (1.2 equiv) were addedto the reaction mixture. The resulting solution was stirred at 90° C.for 16 hours. Reaction mixture was then diluted with Ethyl acetate andwashed with aqueous NaHCO₃ solution, water (×3) and brine. The organiclayer was then dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. Crude mass was then purified by CombiFlash ISCOcolumn, eluting with 3% methanol in DCM to afford 3.

Compound 99

Yellow solid, 125.0 mg, 45.53% yield, 99.48% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.38 (d, J=8.32 Hz, 1H), 8.08 (d, J=6.88 Hz,1H), 7.82 (t, J=7.6 Hz, 1H), 7.70 (s, 1H), 7.36-7.30 (m, 2H), 7.07 (d,J=7.08 Hz, 1H), 5.44-5.42 (m, 1H), 4.20 (s, 2H), 2.95-2.91 (m, 1H),2.77-2.73 (m, 1H), 2.68-2.62 (m, 1H), 2.50-2.49 (m, 2H), 2.37-2.26 (m,4H), 2.14-2.10 (m, 4H), 1.90-1.88 (m, 1H), 1.76-1.74 (m, 4H), 1.57-1.55(m, 2H), 1.28 (s, 3H), 1.11 (s, 3H); LC MS: ES+ 540.3.

Compound 100

Yellow solid, 130.0 mg, 60.22% yield, 98.59% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.88 Hz,1H), 7.81 (t, J=7.58 Hz, 1H), 7.71 (s, 1H), 7.37-7.31 (m, 2H), 7.07 (d,J=7.24 Hz, 1H), 5.43 (dd, J=12.64, 4.8 Hz, 1H), 4.20 (s, 2H), 2.99-2.90(m, 1H), 2.80-2.69 (m, 1H), 2.66-2.62 (m, 1H), 2.50-2.49 (m, 3H),2.34-2.32 (m, 2H), 2.15-1.92 (m, 4H), 1.82-1.78 (m, 2H), 1.29 (s, 3H),1.00 (s, 3H); LC MS: ES+ 526.6.

Compound 101

Yellow solid, 62 mg, 42.40% yield, 97.48% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.08 (s, 1H), 8.35 (d, J=8.24 Hz, 1H), 8.05 (d, J=7.0 Hz,1H), 7.79 (t, J=7.62 Hz, 1H), 7.69 (s, 1H), 7.32 (d, J=6.96 Hz, 1H),7.27 (s, 1H), 7.04 (d, J=7.28 Hz, 1H), 5.40 (dd, J=12.76, 5.08 Hz, 1H),4.17 (s, 2H), 3.14 (s, 3H), 2.93-2.89 (m, 1H), 2.74-2.69 (m, 1H),2.64-2.53 (m, 2H), 2.46-2.05 (m, 7H), 2.07-2.04 (m, 1H), 1.76-1.74 (m,2H), 1.26 (s, 3H), 0.61 (s, 2H), 0.35 (s, 2H); LC MS: ES+ 541.7.

Compound 102

Yellow solid, 70 mg, 41.94% yield, 97.62% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.92 Hz,1H), 7.82 (t, J=7.58 Hz, 1H), 7.73 (s, 1H), 7.35-7.30 (m, 2H), 7.07 (d,J=7.24 Hz, 1H), 5.43 (dd, J=12.56, 4.88 Hz, 1H), 4.20 (s, 2H), 2.98-2.90(m, 1H), 2.79-2.72 (m, 1H), 2.69-2.59 (m, 3H), 2.41-2.30 (m, 4H),2.22-2.18 (m, 2H), 2.09-2.07 (m, 1H), 1.83-1.79 (m, 2H), 1.29 (s, 3H),1.20 (s, 2H), 0.85 (s, 2H); LC MS: Es+ 537.3.

Compound 103

Yellow solid, 59 mg, 34.51% yield, 98.70% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.82 (t, J=7.62 Hz, 1H), 7.71 (s, 1H), 7.35 (d, J=7.28 Hz, 1H),7.30 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.6, 5.04 Hz, 1H),4.20 (s, 2H), 3.02 (s, 3H), 2.94-2.90 (m, 1H), 2.78-2.72 (m, 1H),2.67-2.62 (m, 1H), 2.51-2.50 (m, 2H), 2.36 (s, 2H), 2.33-2.22 (m, 4H),2.10-2.07 (m, 1H), 1.99-1.90 (m, 2H), 1.88-1.82 (m, 2H), 1.78-1.74 (m,2H), 1.66-1.61 (m, 1H), 1.53-1.49 (m, 1H), 1.28 (s, 3H); LC MS: ES+556.7.

Compound 104

Yellow solid, 130.0 mg, 57.40% yield, 94.32% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.82 (t, J=7.62 Hz, 1H), 7.70 (s, 1H), 7.34 (d, J=7.24 Hz, 1H),7.30 (s, 1H), 7.07 (d, J=7.24 Hz, 1H), 5.43 (dd, J=12.64, 4.88 Hz, 1H),4.20 (s, 2H), 2.97-2.90 (m, 1H), 2.77-2.72 (m, 1H), 2.67-2.62 (m, 1H),2.50-2.49 (m, 2H), 2.33-2.29 (m, 4H), 2.09-2.07 (m, 1H), 1.96 (s, 2H),1.79-1.75 (m, 2H), 1.29 (s, 3H), 0.81 (s, 9H); LC MS: ES+ 528.5.

Compound 105

Yellow solid, 90.0 mg, 57.17% yield, 96.90% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.39-8.37 (m, 1H), 8.09-8.07 (m, 1H),7.83-7.81 (m, 1H), 7.71 (s, 1H), 7.36-7.30 (m, 2H), 7.09-7.06 (m, 1H),5.44-5.42 (m, 1H), 4.19 (s, 2H), 3.03-2.91 (m, 1H), 2.77-2.73 (m, 1H),2.67-2.62 (m, 1H), 2.40 (s, 2H), 2.30-2.28 (m, 2H), 2.16-2.15 (m, 2H),2.08-2.07 (m, 1H), 1.78-1.77 (m, 2H), 1.28 (s, 3H), 0.92 (s, 2H), 0.66(s, 2H); LC MS: ES+ 580.3.

Compound 106

Yellow solid, 100.0 mg, 70.18% yield, 97.81% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.38 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.92 Hz,1H), 7.82 (t, J=7.62 Hz, 1H), 7.73 (s, 1H), 7.34 (d, J=7.32 Hz, 1H),7.30 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.84, 5.24 Hz, 1H),4.20 (s, 2H), 2.95-2.90 (m, 1H), 2.78-2.72 (m, 1H), 2.67-2.57 (m, 5H),2.33-2.29 (m, 4H), 2.09-2.07 (m, 1H), 1.83-1.78 (m, 2H), 1.29 (s, 3H),0.97-0.87 (m, 2H), 0.62-0.60 (m, 2H); LC MS: ES+ 530.2.

Example 38. Synthesis of tert-butyl4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazine-1-carboxylate(Compound 1071

Step 1: Synthesis of tert-butyl4-(4-(chloromethyl)benzyl)piperazine-1-carboxylate: To a stirredsolution of tert-butyl piperazine-1-carboxylate 1 (10 g, 53.69 mmol) inDMF (100 mL) was added DIPEA (20.82 g, 161.07 mmol, 28.06 mL) andstirred for 5 min. Then 1,4-bis(chloromethyl)benzene 2 (9.40 g, 53.69mmol, 6.62 mL) was added and the reaction was heated at 60° C. for 16hours. After completion of the reaction (monitored by TLC), the reactionmixture was diluted with ethyl acetate and washed with water and brine,dried over sodium sulfate and concentrated. Crude material was purifiedby column chromatography (100-200 silica, 25-30% EtOAc in hexane) toafford tert-butyl4-[[4-(chloromethyl)phenyl]methyl]piperazine-1-carboxylate 3 (7 g, 19.39mmol, 36.12% yield, 90% purity) as off white solid. LC MS: ES+ 324.9.

Step 2: Synthesis of tert-butyl4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazine-1-carboxylate:To a stirred solution of tert-butyl4-[[4-(chloromethyl)phenyl]methyl]piperazine-1-carboxylate 3 (4 g, 12.31mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one4 (7.27 g, 24.63 mmol) in ethanol (20 mL) and Toluene (40 mL) was addedPotassium phosphate tribasic anhydrous (7.84 g, 36.94 mmol) and thereaction mass was degassed under nitrogen atmosphere over 10 minutes.Tri-o-Tolyl phosphine (749.58 mg, 2.46 mmol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (1.13 g, 1.23 mmol)was then added to this reaction mass and it was heated at 90° C. overnight. Then the reaction mixture was filtered through sintered funnelusing celite bed. Filtrate was diluted with ethyl acetate and washedwith water. The organic part was dried over Na₂SO₄ and evaporated underreduced pressure. Crude thus obtained was purified by combi-flashchromatography (eluted at 0-30% EA/DCM) to get the pure compoundtert-butyl4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazine-1-carboxylate5 (3.2 g, 6.29 mmol, 51.12% yield, 90% purity) as yellow solid. LC MS:ES+ 458.4.

Step 3: Synthesis of tert-butyl4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazine-1-carboxylate:To a stirred solution of tert-butyl4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazine-1-carboxylate5 (3.1 g, 6.78 mmol) in dry THF (80 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (2.34 g, 101.63 mmol) at 0° C.and stirred for 15 minutes followed by the addition of3-bromopiperidine-2,6-dione 6 (6.50 g, 33.88 mmol). Resulting reactionmixture was stirred at 70° C. for 1 hour. After complete conversion,reaction mixture was quenched with ice water and extracted with ethylacetate (2×100 mL). Combined organic layer was separated, dried oversodium sulfate and concentrated. Crude reaction mass was purified bycombiflash column chromatography (0-30% Ethyl acetate in DCM as eluent)to afford tert-butyl4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazine-1-carboxylateCompound 107 (2.3 g, 3.85 mmol, 56.83% yield, 95.20% purity) as yellowsolid. ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.12 Hz,1H), 8.07 (d, J=6.88 Hz, 1H), 7.80 (t, J=7.58 Hz, 1H), 7.40 (d, J=7.2Hz, 1H), 7.25-7.09 (m, 5H), 5.44 (dd, J=12.64, 4.76 Hz, 1H), 4.37 (s,2H), 3.38 (s, 2H), 3.25 (s, 4H), 2.98-2.90 (m, 1H), 2.79-2.69 (m, 1H),2.66-2.62 (m, 1H), 2.24 (s, 4H), 2.10-2.07 (m, 1H), 1.36 (s, 9H); LC MS:ES+ 569.3.

Step 4: Synthesis of3-(2-oxo-6-(4-(piperazin-1-ylmethyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dionehydrochloride: To a stirred solution of tert-butyl4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazine-1-carboxylate7 (2.3 g, 4.04 mmol) in 1,4-DIOXANE (20 mL) was added DIOXANE-HCL (50mL) at 0° C. and stirred the reaction mass was stirred at roomtemperature 4 hours. Reaction mass was concentrated under reducedpressure, crude was triturated with ether-pentane to afford desiredcompound3-[2-oxo-6-[[4-(piperazin-1-ylmethyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione;hydrochloride Compound 295 (2 g, 3.51 mmol, 86.76% yield, 95% purity) aslight yellow solid. LC MS: ES+ 469.4.

Example 39. General Synthesis of Compound 108-Compound 112

To an equi-molar mixture of Amine and Acid DMF (6 mL/mmol) were addedHATU (1.5 equiv) and DIPEA (5.0 equiv) at 0° C. The resulting solutionwas stirred at ambient temperature for 16 hours. The reaction mixturewas then diluted with Ethyl acetate and washed with aqueous NaHCO₃solution, water (×3) and brine. The organic layer was then dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. Crude mass wasthen purified by CombiFlash ISCO column, eluting with 2% methanol in DCMto afford 3.

Compound 108:

Yellow solid, 23.0 mg, 21.09% yield, 92.73% purity. 1H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.33 (d, J=8.32 Hz, 1H), 8.07 (d, J=6.96 Hz,1H), 7.81 (t, J=7.6 Hz, 1H), 7.40 (d, J=7.44 Hz, 1H), 7.25-7.23 (m, 2H),7.20-7.18 (m, 2H), 7.10 (d, J=7.32 Hz, 1H), 5.44 (dd, J=13.52, 5.4 Hz,1H), 4.38 (s, 2H), 3.40-3.36 (m, 6H), 2.95-2.92 (m, 1H), 2.76-2.73 (m,1H), 2.66-2.63 (m, 1H), 2.32-2.28 (m, 2H), 2.25-2.21 (m, 2H), 2.10-2.07(m, 1H), 1.94 (s, 3H); LC MS:511.2.

Compound 109:

Yellow solid, 45.0 mg, 36.97% yield, 100% purity. 1H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.33 (d, J=8.36 Hz, 1H), 8.07 (d, J=6.96 Hz,1H), 7.81 (t, J=7.60 Hz, 1H), 7.41 (d, J=7.4 Hz, 1H), 7.26-7.18 (m, 4H),7.10 (d, J=7.08 Hz, 1H), 5.44-5.43 (m, 1H), 4.47 (q, J=10.28 Hz, 2H),4.38 (s, 2H), 3.44 (s, 2H), 3.19 (brs, 4H), 2.96-2.92 (m, 1H), 2.76-2.73(m, 1H), 2.67-2.62 (m, 1H), 2.39 (brs, 4H), 2.09-2.07 (m, 1H); LC MS:ES+ 615.2.

Compound 110:

Yellow solid, 40.0 mg, 33.04% yield, 92.36% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.24 Hz, 1H), 8.07 (d, J=7.0 Hz,1H), 7.80 (t, J=7.66 Hz, 1H), 7.40 (d, J=7.32 Hz, 1H), 7.25-7.11 (m,5H), 5.44 (dd, J=12, 4.44 Hz, 1H), 4.37 (s, 2H), 3.39-3.32 (m, 4H),3.20-3.18 (m, 2H), 2.94-2.90 (m, 1H), 2.76-2.73 (m, 1H), 2.66-2.62 (m,1H), 2.35-2.30 (m, 2H), 2.30-2.25 (m, 4H), 2.10-2.08 (m, 1H), 1.91-1.84(m, 1H), 1.76-1.72 (m, 2H), 1.59-1.56 (m, 1H), 1.29 (s, 3H); LC MS: ES+565.6.

Compound 111:

Yellow solid, 70.0 mg, 60.98% yield, 98.78% purity. 1H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.32 (d, J=8.28 Hz, 1H), 8.07 (d, J=6.96 Hz,1H), 7.81 (t, J=7.56 Hz, 1H), 7.43-7.39 (m, 4H), 7.36-7.33 (m, 2H),7.25-7.18 (m, 4H), 7.10 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.8, 5.28 Hz,1H), 4.38 (s, 2H), 3.57 (brs, 2H), 3.42 (s, 2H), 2.94-2.90 (m, 1H),2.76-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.34-2.32 (m, 4H), 2.11-2.07 (m,1H); LC MS: ES+ 573.3.

Compound 112:

Yellow solid, 55.0 mg, 49.51% yield, 95.65% purity. 1H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.32 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.96 Hz,1H), 7.80 (t, J=7.68 Hz, 1H), 7.41 (d, J=7.32 Hz, 1H), 7.26-7.19 (m,4H), 7.10 (d, J=7.28 Hz, 1H), 5.44 (dd, J=12.72, 5.08 Hz, 1H), 4.38 (s,2H), 3.61 (brs, 2H), 3.41 (s, 4H), 2.96-2.92 (m, 1H), 2.77-2.73 (m, 1H),2.67-2.63 (m, 1H), 2.33-2.25 (m, 4H), 2.10-2.07 (m, 1H), 1.92-1.89 (m,1H), 0.69-0.65 (m, 4H); LC MS: ES+ 537.2.

Example 40. General Synthesis of (Compound 113)

To a stirred solution of Amine (1.0 equiv) in THF (6 mL/mmol) was addedTriethylamine (2.0 equiv) at 0° C. Then Aldehyde (1.0 equiv),Phenylsilane (1.0 equiv) and Dibutyltindichloride (1.2 equiv) were addedto the reaction mixture. The resulting solution was stirred at 90° C.for 16 hours. Reaction mixture was then diluted with Ethyl acetate andwashed with aqueous NaHCO₃ solution, water (×3) and brine. The organiclayer was then dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. Crude mass was then purified by CombiFlash ISCOcolumn, eluting with 2-3% methanol in DCM to afford the final compound.

Compound 113

Yellow solid, 75.0 mg, 54.68% yield, 98.08% purity. 1H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.32 (d, J=8.20 Hz, 1H), 8.07 (d, J=6.96 Hz,1H), 7.80 (t, J=7.76 Hz, 1H), 7.40 (d, J=7.28 Hz, 1H), 7.22-7.16 (m,4H), 7.10 (d, J=7.08 Hz, 1H), 5.45-5.41 (m, 1H), 4.37 (s, 2H), 3.37 (s,2H), 2.95-2.92 (m, 1H), 2.76-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.63-2.50(m, 1H), 2.40-2.32 (m, 7H), 2.12-2.09 (m, 3H), 0.77 (brm, 1H), 0.42(brs, 2H), 0.03 (brs, 2H); LC MS: ES+ 523.2.

Example 41. General Synthesis of Compound 114-Compound 123

Step 1: Synthesis of4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzaldehyde: To astirred solution of 4-(chloromethyl)benzaldehyde 1 (9.5 g, 61.45 mmol)and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one2 (36.27 g, 122.90 mmol) in ethanol (30 mL) and Toluene (60.0 mL) wasadded Potassium phosphate tribasic anhydrous (39.13 g, 184.35 mmol) andthe reaction mass was degassed under nitrogen atmosphere over 10minutes. Tri-o-Tolyl phosphine (3.74 g, 12.29 mmol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (5.63 g, 6.15 mmol)were added to this reaction mass and resultant reaction mixture heatedat 90° C. over night. Reaction mixture was filtered through sinteredfunnel using celite bed and filtrate was diluted with ethyl acetate.Organic part was separated and washed with water. It was dried overNa₂SO₄ and evaporated under reduced pressure. Crude material waspurified by combi-flash chromatography to get the desired compound4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]benzaldehyde 3 (5.5 g, 7.27mmol, 11.84% yield, 38% purity) as yellow solid. LC MS: ES+ 288.0.

Step 2: Synthesis of4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzaldehyde:To a stirred solution of4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]benzaldehyde 3 (3.0 g, 10.44mmol) in dry THF (30.0 mL), Sodium hydride (in oil dispersion) 60%dispersion in mineral oil (4.00 g, 100.02 mmol, 60% purity) was added at0° C. and stirred for 15 minutes followed by the addition of3-bromopiperidine-2,6-dione 4 (10.02 g, 52.21 mmol). Resulting reactionmixture was stirred at 70° C. for 1.5 hour. Reaction mixture was heatedto reflux for 2 hours. After complete conversion as evidenced from LCMS,reaction mixture was quenched with water and extracted with ethylacetate (2×20 mL). Combined organic layer was separated, dried oversodium sulfate and concentrated. Crude reaction mass was purified bycombi-flash (2.5% MeOH in DCM as eluent) to afford4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]benzaldehyde5 (1.4 g, 2.81 mmol, 26.92% yield, 80% purity) as yellow solid. LC MS:ES+ 399.2.

Step 3: Synthesis of analogs: To a stirred solution of Amine (1.0 equiv)in THF (6 mL/mmol) was added Triethylamine (2.0 equiv) at 0° C. (whenamine is hydrochloride salt). Then Aldehyde (1.0 equiv), Phenylsilane(1.0 equiv) and Dibutyltindichloride (1.2 equiv) were added to thereaction mixture. The resulting solution was stirred at 90° C. for 16hours. Reaction mixture was then diluted with Ethyl acetate and washedwith aqueous NaHCO₃ solution, water (×3) and brine. The organic layerwas then dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. Crude mass was then purified by CombiFlash ISCO column,eluting with 2-3% methanol in DCM to afford the analog.

Compound 114

Yellow solid, 46.0 mg, 8.25% yield, 95.00% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.07 (d, J=7.0 Hz,1H), 7.80 (t, J=7.92 Hz, 1H), 7.40 (d, J=7.36 Hz, 1H), 7.24-7.16 (m,4H), 7.10 (d, J=7.20 Hz, 1H), 5.45-5.42 (m, 1H), 4.37 (s, 2H), 3.38 (s,2H), 3.32 (s, 3H), 2.95-2.90 (m, 1H), 2.76-2.73 (m, 1H), 2.70-2.65 (m,1H), 2.65-2.62 (m, 1H), 2.40-2.30 (m, 5H), 2.17-2.10 (m, 2H), 2.10-2.07(m, 1H); LC MS: ES− 481.2.

Compound 115

Yellow solid, 70.0 mg, 10.99% yield, 98.76% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.92 Hz,1H), 7.81 (t, J=7.44 Hz, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.24-7.16 (m, 4H),7.10 (d, J=7.24 Hz, 1H), 5.44 (dd, J=12.72, 4.96 Hz, 1H), 4.37 (s, 2H),4.15 (s, 2H), 3.35 (s, 2H), 2.98-2.90 (m, 1H), 2.79-2.73 (m, 1H),2.69-2.62 (m, 1H), 2.50-2.42 (m, 2H), 2.14-2.07 (m, 3H), 1.82-1.75 (m,2H), 1.68-1.67 (m, 2H); LC MS: ES+ 496.2.

Compound 116

Yellow solid, 76.0 mg, 12.35% yield, 99.00% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.16 Hz, 1H), 8.07 (d, J=6.88 Hz,1H), 7.80 (t, J=7.6 Hz, 1H), 7.40 (d, J=7.24 Hz, 1H), 7.26-7.19 (m, 4H),7.10 (d, J=7.24 Hz, 1H), 5.45-5.41 (m, 1H), 4.38 (s, 2H), 3.44 (s, 2H),3.20-2.16 (m, 2H), 2.89 (s, 3H), 2.78 (s, 4H), 2.74-2.69 (m, 1H),2.66-2.62 (m, 2H), 2.10-2.07 (m, 1H); LC MS: ES+ 497.2.

Compound 117

Yellow solid, 42.0 mg, 7.03% yield, 95.09% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.34 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.88 Hz,1H), 7.82 (t, J=7.2 Hz, 1H), 7.42 (d, J=6.68 Hz, 1H), 7.31-7.26 (m, 4H),7.17-7.10 (m, 5H), 5.45-5.43 (m, 1H), 4.39 (s, 2H), 3.78 (s, 6H),3.05-2.95 (m, 1H), 2.92-2.87 (m, 1H), 2.76-2.66 (m, 1H), 2.10-2.07 (m,1H); LC MS: ES+ 502.2.

Compound 118

Yellow solid, 50.0 mg, 14.70% yield, 98.09% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.16 Hz, 1H), 8.07 (d, J=6.8 Hz,1H), 7.80 (t, J=7.56 Hz, 1H), 7.41 (dd, J=7.28 Hz, 1H), 7.26-7.09 (m,6H), 6.99-6.94 (m, 3H), 5.45-5.42 (m, 1H), 4.38 (s, 2H), 3.96 (br s,2H), 3.69 (s, 2H), 3.53 (s, 2H), 2.96-2.90 (m, 3H), 2.76-2.62 (m, 2H),2.08-2.07 (m, 1H); LC MS: ES+ 532.2.

Compound 119

Yellow solid, 50.0 mg, 23.20% yield, 98.45% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.30 (d, J=8.2 Hz, 1H), 8.07 (d, J=6.96 Hz,1H), 7.79-7.77 (m, 1H), 7.39-7.32 (m, 3H), 7.24-7.18 (m, 4H), 7.14-7.09(m, 3H), 5.46-5.43 (m, 1H), 4.47-4.44 (m, 1H), 4.37 (s, 2H), 3.88-3.86(m, 1H), 3.64-3.58 (m, 1H), 3.47-3.38 (m, 2H), 2.99-2.91 (m, 1H),2.79-2.73 (m, 2H), 2.69-2.64 (m, 2H), 2.09-2.07 (m, 2H), 1.93-1.87 (m,1H); LC MS: ES+ 564.2.

Compound 120

Yellow solid, 32.0 mg, 7.58% yield, 97.99% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.31 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.96 Hz,1H), 7.80 (t, J=7.52 Hz, 1H), 7.40 (d, J=7.36 Hz, 1H), 7.23-7.15 (m,4H), 7.11-7.05 (m, 3H), 6.83-6.79 (m, 2H), 5.44-5.41 (m, 1H), 4.73-4.70(m, 1H), 4.37 (s, 2H), 3.65 (t, J=6.64 Hz, 2H), 3.54 (s, 2H), 2.97-2.92(m, 3H), 2.76-2.73 (m, 1H), 2.67-2.62 (m, 1H), 2.10-2.07 (m, 1H); LC MS:ES+ 550.3.

Compound 121

Yellow solid, 65.0 mg, 17.10% yield, 94.39% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.33 (d, J=8.24 Hz, 1H), 8.07 (d, J=7.0 Hz,1H), 7.81 (t, J=7.6 Hz, 1H), 7.41 (d, J=7.32 Hz, 1H), 7.29-7.24 (m, 4H),7.10 (d, J=7.32 Hz, 1H), 5.47-5.43 (m, 1H), 4.39 (s, 2H), 4.10 (t,J=5.08 Hz, 2H), 3.78 (s, 2H), 3.69 (s, 2H), 2.99-2.90 (m, 1H), 2.86 (t,J=5.24 Hz, 1H), 2.78-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.08-2.07 (m, 1H);LC MS: ES+ 575.6.

Compound 122

Yellow solid, 45.0 mg, 17.16% yield, 99.09% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.33 (d, J=8.28 Hz, 1H), 8.07 (dd, J=6.96 Hz,1H), 7.80 (t, J=7.62 Hz, 1H), 7.41 (d, J=7.32 Hz, 1H), 7.26-7.20 (m,4H), 7.10 (d, J=7.28 Hz, 1H), 5.44 (dd, J=12.24, 4.8 Hz, 1H), 4.38 (s,2H), 3.58 (s, 2H), 3.05 (br s, 4H), 2.95-2.90 (m, 1H), 2.81-2.79 (m,5H), 2.73-2.62 (m, 1H), 2.10-2.07 (m, 1H); LC MS: ES− 516.2.

Compound 123

Yellow solid, 30.0 mg, 9.30% yield, 94.10% purity. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.07 (d, J=6.92 Hz,1H), 7.80 (t, J=7.56 Hz, 1H), 7.40 (d, J=7.0 Hz, 1H), 7.24-7.21 (m, 4H),7.10 (d, J=7.24 Hz, 1H), 5.44 (dd, J=12.4, 5.12 Hz, 1H), 4.37 (s, 2H),3.65 (t, J=5.92 Hz, 1H), 3.54-3.52 (m, 4H), 2.95-2.91 (m, 1H), 2.77-2.73(m, 1H), 2.66-2.62 (m, 1H), 2.52-2.43 (m, 4H), 2.10-2.07 (m, 2H); LC MS:ES+ 484.5.

Example 42. Synthesis of Synthesis of methyl1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indole-6-carboxylate (Compound124)

Step 1: Synthesis of 2-oxo-1H-benzo[cd]indole-6-carboxylate (2): Astirred solution of 6-bromo-1H-benzo[cd]indol-2-one (1) (1 g, 4.03 mol)and DPPP (332.51 mg, 806.21 umol) in Methanol (30 mL) in a PARRautoclave vessel was degassed with Argon for 5 minutes, followed byaddition of TEA (1.63 g, 16.12 mmol, 2.25 mL) and Palladium (II) acetate(90.50 mg, 403.10 umol). The resultant reaction mixture was heated at100° C. and for 16 hr under 70 psi of Carbon monoxide atmosphere in parauto clave. After completion of the reaction mixture TLC showed newspot, the reaction mixture was filtered through celite pad and filtratewas concentrated to get crude mass which was purified by combiflashchromatography using 10% EtOAc-Hexane as eluent to afford methyl2-oxo-1H-benzo[cd]indole-6-carboxylate (2) (800 mg, 69.88% yield) asyellow solid. LC MS: ES+ 228.3.

Step 2: Synthesis of methyl1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indole-6-carboxylate (4): To astirred solution of methyl 2-oxo-1H-benzo[cd]indole-6-carboxylate (2)(100 mg, 440.11 umol) in DMF (3 mL) was added Sodium hydride (60%dispersion in mineral oil) (33.73 mg, 880.22 umol) and stirred at 70° C.for 30 min. Then 3-bromopiperidine-2,6-dione (3) (84.51 mg, 440.11 umol)was added and the reaction mixture was allowed to stir at that temp for16 h. TLC showed formation of a new polar spot along with un-reacted SM.The reaction mixture was quenched with water and extracted with ethylacetate. The organic part was dried over sodium sulphate andconcentrated. The crude thus obtained was purified by Prep TLC plate in2% MeOH in DCM to afford methyl1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indole-6-carboxylate Compound124 (13 mg, 7.86% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ11.15 (s, 1H), 8.98 (d, J=Hz, 1H), 8.31 (d, J=Hz, 1H), 8.16 (d, J=Hz,1H), 7.95 (t, J=Hz, 1H), 7.26 (d, J=Hz, 1H), 5.50-5.47 (m, 1H), 3.92 (s,3H), 3.04-2.82 (m, 1H), 2.77-2.71 (m, 1H), 2.66-2.64 (m, 1H), 2.12-2.10(m, 1H); LC MS: ES+ 339.1.

Example 43. Synthesis of3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 125)

Step 1: Synthesis of6-(azidomethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (2): Toa stirred solution of6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1)(600 mg, 1.78 mmol) in DMF (10 mL) was added Sodium azide (346.41 mg,5.33 mmol) under cooling condition and the resultant reaction mixturewas stirred at room temperature for 16 hr. After completion (monitoredby TLC) the reaction mixture was diluted with EtOAc and washed withwater and brine, dried over sodium sulphate and concentrated underreduced pressure to afford6-(azidomethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (2) (500mg, 72.75% yield) as sticky solid. LC MS: ES+ 345.3.

Step 2: Synthesis of tert-butyl4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]triazol-4-yl]piperidine-1-carboxylate(4): To a stirred solution of6-(azidomethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (2) (500mg, 1.45 mmol) and tert-butyl 4-ethynylpiperidine-1-carboxylate (3)(303.87 mg, 1.45 mmol) in THF (12 mL) a solution of copper; sulfate;pentahydrate (36.25 mg, 145.19 umol) in water (3 mL) was added andstirred for 15 minutes followed by the addition of sodium;(2R)-2-[1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (115.06 mg,580.78 umol). The resultant reaction mixture was stirred at RT for 16hours. After completion (monitored by TLC) the reaction mixture wasfiltered through celite bed and the filtrate was concentrated underreduced pressure. The crude thus obtained was purified by columnchromatography (Silica, Gradient 0-3% MeOH in DCM) to afford tert-butyl4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]triazol-4-yl]piperidine-1-carboxylate(4) (500 mg, 61.15% yield) as light yellow solid. LC MS: ES+ 554.6.

Step 3: Synthesis of1-[(4-methoxyphenyl)methyl]-6-[[4-(4-piperidyl)triazol-1-yl]methyl]benzo[cd]indol-2-one;hydrochloride (5): To a stirred solution of tert-butyl4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]triazol-4-yl]piperidine-1-carboxylate(4) (150 mg, 270.93 umol) in Dioxane (2 mL) was added Dioxane-HCl (4M)(4 mL) under cooling condition and the resultant reaction mixture wasstirred at RT for 4 hours. After completion (monitored by TLC) thereaction mixture was concentrated under reduced pressure. The crude wastriturated with Ether-Pentane to afford1-[(4-methoxyphenyl)methyl]-6-[[4-(4-piperidyl)triazol-1-yl]methyl]benzo[cd]indol-2-one;hydrochloride (5) (110 mg, 69.4% Yield) as light yellow solid. LC MS:ES+ 454.5.

Step 4: Synthesis of1-[(4-methoxyphenyl)methyl]-6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]benzo[cd]indol-2-one(7): To the stirred solution of1-[(4-methoxyphenyl)methyl]-6-[[4-(4-piperidyl)triazol-1-yl]methyl]benzo[cd]indol-2-one;hydrochloride (5) (600 mg, 1.22 mmol) and 1-methylcyclobutanecarboxylicacid (6) (139.77 mg, 1.22 mmol) in DMF (10 mL) was added DIPEA (791.27mg, 6.12 mmol, 1.07 mL) and stirred for 15 minutes followed by theaddition of HATU (558.71 mg, 1.47 mmol) and was allowed to stir for 16hr at RT. After completion (monitored by LCMS), the reaction mixture wasdiluted with Ethyl acetate and washed with cold water, brine, dried oversodium sulfate and concentrated under reduced pressure. The crude thusobtained was purified by column chromatography (silica, gradient: 0-3%MeOH in DCM) to afford1-[(4-methoxyphenyl)methyl]-6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]benzo[cd]indol-2-one(7) (400 mg, 53.4% yield) as gummy solid. LC MS: ES+ 550.3.

Step 5: Synthesis of6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]-1H-benzo[cd]indol-2-one(8): To a stirred solution of compound1-[(4-methoxyphenyl)methyl]-6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]benzo[cd]indol-2-one(7) (400 mg, 727.72 umol) in TFA (4.0 mL) was addedTrifluoromethanesulfonic acid (546.08 mg, 3.64 mmol, 319.35 uL) undercooling condition and the resultant reaction mixture was stirred at RTfor 16 hr. After completion (monitored by TLC) the reaction mixture wasconcentrated under reduced pressure and crude mass was basified withsaturated sodium bicarbonate solution and extracted with ethyl acetate.The layers were separated and the organic part was dried over sodiumsulphate and concentrated under reduced pressure. Crude thus obtainedwas purified by Combiflash column (Gradient 0-3% MeOH in DCM) to afford6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]-1H-benzo[cd]indol-2-one(8) (300 mg, 91.18% yield) as light yellow solid. LC MS: ES+ 430.4.

Step 6: Synthesis of3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]-1H-benzo[cd]indol-2-one(8) (140 mg, 325.95 umol) in THF (5 mL) was added Sodium hydride 60%dispersion in mineral oil (22.48 mg, 977.85 umol) at 0° C. and stirredfor 5 min. Then 3-bromopiperidine-2,6-dione (9) (125.17 mg, 651.90 umol)was added under cooling condition and the reaction mixture was stirredat 70° C. for 60 min. After completion (monitored by TLC) the reactionmixture was quenched in ice and extracted with ethyl acetate. Theorganic part was further washed with water and brine, dried over sodiumsulfate and concentrated. The crude was purified by Prep TCL Plate in2.5% MeOH in DCM to afford3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 125 (30 mg, 17% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.13 (s, 1H), 8.43 (d, J=8.28 Hz, 1H), 8.12 (d, J=7.0 Hz,1H), 7.96 (s, 1H), 7.88 (t, J=7.66 Hz, 1H), 7.58 (d, J=7.44 Hz, 1H),7.17 (d, J=7.36 Hz, 1H), 5.46 (dd, J=12.64, 4.84 Hz, 1H), 4.30-4.28 (m,1H), 3.51-3.49 (m, 1H), 3.03-2.63 (m, 6H), 2.49-2.32 (m, 2H), 2.09-2.07(m, 1H), 1.93-1.85 (m, 3H), 1.79-1.73 (m, 2H), 1.61-1.57 (m, 1H),1.42-1.39 (m, 2H), 1.31 (s, 3H); LC MS: ES+ 542.3.

Example 44. Synthesis of3-[6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 126)

Step 1: Synthesis1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazole-4-carbaldehyde(3): To the stirred solution of1-(4-methyl-4-piperidyl)pyrazole-4-carbaldehyde (1) (325 mg, 1.68 mmol)in NMP (2.0 mL) was added N,N-Diisopropylethylamine (652.08 mg, 5.05mmol, 878.82 uL) drop wise followed by the addition of2,3-difluoropyridine (2) (193.54 mg, 1.68 mmol) and resulting solutionwas heated at 135° C. in a sealed tube for 12 hours. After completion ofreaction (evidenced from LC MS), reaction mix was diluted with ethylacetate (30 mL) and washed with cold water (2×15 mL). Organic phase wasseparated, dried over anhydrous sodium sulfate and evaporated undervacuum. Crude thus obtained was purified by flash chromatography(silica, gradient: 0 to 70% EtOAc in Hexane) to afford1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazole-4-carbaldehyde(3) (300 mg, 1.03 mmol, 61.25% yield, 99% purity). LC MS: ES+ 289.4.

Step 2: Synthesis of6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]-hydroxy-methyl]-1H-benzo[cd]indol-2-one(5): To the stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (4) (270mg, 1.09 mmol) in dry grade THF (5.0 mL), was added Phenyllithium, 1.9Min di-n-butyl ether (91.47 mg, 1.09 mmol, 112.93 uL) at −78° C. under N2atmosphere and the reaction was stirred at the same temperature for 30minutes followed by the addition of n-Butyllithium (76.69 mg, 1.20 mmol)same temperature. After complete addition, the temperature was allowedto increase to −40° C. and the reaction mixture was stirred at the sametemperature for 30 minutes. After getting the dess-bormo spot in TLC(30% ethyl acetate in Hexane) solution of1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazole-4-carbaldehyde(3) (260.45 mg, 903.36 umol) in dry THF (5.0 mL) was added at −78° C.and stirring was continued for 16 hr at room temperature. Aftercompletion of reaction (evidenced from TLC and LC MS), the reactionmixture was quenched with saturated ammonium chloride solution andextracted with ethyl acetate (2×40 mL). Organic phase was washed withwater (2×20 mL) and separated, dried over anhydrous sodium sulphate andevaporated under reduced pressure to obtain the crude compound which waspurified by flash chromatography (silica, gradient: 0-5% MeOH in DCM) toafford6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]-hydroxy-methyl]-1H-benzo[cd]indol-2-one(5) (88 mg, 190.43 umol, 17.50% yield) as brown solid and stored atambient temperature in a round bottomed flask. LC MS: ES+ 458.5.

Step 3: Synthesis of6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(6): To the stirred solution of6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]-hydroxy-methyl]-1H-benzo[cd]indol-2-one(5) (86 mg, 187.98 umol) in DCE (2.0 mL) was added triethylsilane (87.43mg, 751.92 umol, 120.10 uL) and Trifluoroacetic acid, 99% (171.47 mg,1.50 mmol, 115.86 uL). Resulting solution heated at 70° C. undermicrowave condition for 30 mins. After completion of reaction (evidencedfrom TLC and LC MS), volatiles were removed. Solid residue was redissolved in ethyl acetate (50 mL) and washed with saturated bicarbonatesolution. Organic phase was separated, died over anhydrous sodiumsulfate and concentrated. Crude reaction mass was purified by flashchromatography (silica, gradient: 0-5% MeOH in DCM) to afford6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(6) (56 mg, 120.50 umol, 64.10% yield) as yellow solid which was kept atambient temperature in a round bottomed flask. LC MS: ES+ 442.2.

Step 4: Synthesis of3-[6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a ice cooled solution of6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(55.00 mg, 124.58 umol) (6) in dry THF (3 mL), Sodium hydride (60%dispersion in mineral oil) (28.64 mg, 1.25 mmol) was added portion wise,maintaining the temp <5° C. Once the addition is over, the resultantmixture was stirred for 15 minutes at RT. Then the reaction mixture wasagain cooled to 0° C. and 3-bromopiperidine-2,6-dione (7) (119.60 mg,622.88 umol) was added to it portion wise. After complete addition,resulting solution was heated at 70° C. for 2 hour. After completion(evidenced from TLC), the reaction mixture was again cooled to 0° C. andquenched with ice cooled water (10 mL). Aqueous part was extracted withethyl acetate (2×20 mL). Combined extracts was dried over anhydroussodium sulfate and concentrated under reduced pressure. Crude mass waspurified by Preparative TLC (gradient: 2.5% MeOH in DCM) to3-[6-[[1-[1-(3-fluoro-2-pyridyl)-4-methyl-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 126 (30 mg, 54.02 umol, 43.37% yield) as yellow solid which wasstored in a round bottomed flask at 5° C. inside a refrigerator. ¹H NMR(400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.40 (d, J=8.24 Hz, 1H), 8.08 (d,J=7.08 Hz, 1H), 7.98 (d, J=4.6 Hz, 1H), 7.84-7.81 (m, 2H), 7.50-7.45 (m,1H), 7.35-7.33 (m, 2H), 7.07 (d, J=7.32 Hz, 1H), 6.86-6.83 (m, 1H), 5.43(dd, J=12.68, 4.96 Hz, 1H), 4.21 (s, 2H), 3.51 (m, 2H), 3.21-3.16 (m,2H), 2.94 (m, 1H), 2.75-2.61 (m, 3H), 2.42-2.40 (m, 2H), 2.09-2.07 (m,1H), 1.92-1.88 (m, 2H), 1.38 (s, 3H); LC MS: ES+ 553.3.

Example 45. Synthesis of3-[6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 127)

Step 1: Synthesis of tert-butyl4-ethynyl-4-methyl-piperidine-1-carboxylate (3): To the stirred solutionof tert-butyl 4-formyl-4-methyl-piperidine-1-carboxylate 1 (2.0 g, 8.80mmol) in anhydrous Methanol (10.0 mL) was added Potassium carbonate,anhydrous, 99% (2.43 g, 17.60 mmol, 1.06 mL) and stirred the at roomtemperature for 30 mins. Dimethyl (1-diazo-2-oxopropyl)phosphonate 2(2.03 g, 10.56 mmol) was added drop wise to the reaction mix and stirredthe reaction mix at rt for overnight. After completion of reaction(evidenced from TLC), volatiles were removed under vacuum. Solid thusobtained was dissolved in ethyl acetate (100 mL) and washed withsaturated NaHCO₃ solution. Organic portion was separated, dried overanhydrous Na₂SO₄ and evaporated under vacuum to afford the crudecompound tert-butyl 4-ethynyl-4-methyl-piperidine-1-carboxylate 3 (1.95g, 7.86 mmol, 89.32% yield) which is used for the next step without anypurification. LC MS: ES+ 224.2.

Step 2: Synthesis of tert-butyl4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]triazol-4-yl]-4-methyl-piperidine-1-carboxylate(5): To the stirred solution of tert-butyl4-ethynyl-4-methyl-piperidine-1-carboxylate 3 (800 mg, 3.58 mmol) in THF(15.0 mL) was added6-(azidomethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 4(616.84 mg, 1.79 mmol) at room temperature. After that, solution ofcopper; sulfate; pentahydrate (111.81 mg, 447.81 umol) in Water (5.0 mL)was added drop wise added to the reaction mix followed by sodium;(2R)-2-[(1S)-1,2-di hydroxy ethyl]-4-hydroxy-5-oxo-2H-furan-3-olate(141.94 mg, 716.49 umol) and stirring was continued for 4 hours at sametemperature. After completion of reaction, then the reaction mix wasdiluted with ethyl acetate (40 mL) and filtered through bed of celite.Filtrate was collected and evaporated under vacuum. Crude thus obtainedwas purified by flash chromatography (100-200 silica; 0-60% Ethylacetate in Hexane) to afford tert-butyl4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]triazol-4-yl]-4-methyl-piperidine-1-carboxylate5 (900 mg, 1.49 mmol) as yellow solid and stored in a round bottomedflask at ambient temperature. LC MS: ES+ 568.2.

Step 3: Synthesis of1-[(4-methoxyphenyl)methyl]-6-[[4-(4-methyl-4-piperidyl)triazol-1-yl]methyl]benzo[cd]indol-2-one;hydrochloride (6): To the cold solution of tert-butyl4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]triazol-4-yl]-4-methyl-piperidine-1-carboxylate5 (900 mg, 1.59 mmol) in dioxane (5 mL) 4.0 M in Dioxane-HCl (1.59 mmol,10.0 mL) was added drop wise and stirred the reaction at rt for 4 hours.After completion of reaction (evidenced from LCMS) volatiles wereevaporated under reduced pressure. Solid material thus obtained waswashed with diethyl ether (50 mL) and dried under reduced pressure toafford1-[(4-methoxyphenyl)methyl]-6-[[4-(4-methyl-4-piperidyl)triazol-1-yl]methyl]benzo[cd]indol-2one; hydrochloride 6 (830 mg, 1.49 mmol, 93.96% yield) as yellow solidand stored in round bottom flask at 5° C. in refrigerator. LC MS: ES+468.4.

Step 4: Synthesis of1-[(4-methoxyphenyl)methyl]-6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]benzo[cd]indol-2-one(8): To the stirred solution of1-(trifluoromethyl)cyclopropanecarboxylic acid 7 (100.89 mg, 654.73umol) in dry grade DMF (5.0 mL) was added HATU (339.48 mg, 892.82 umol)and stirred for 15 minutes at room temperature under N₂ atmosphere.Solution of1-[(4-methoxyphenyl)methyl]-6-[[4-(4-methyl-4-piperidyl)triazol-1-yl]methyl]benzo[cd]indol-2-one;hydrochloride 6 (300 mg, 595.21 umol) andN-ethyl-N-isopropyl-propan-2-amine (384.63 mg, 2.98 mmol, 518.38 uL) indry grade DMF (3.0 mL) was added to the resulting solution at 0° C. andstirred for another 12 hours at room temperature. After completion ofreaction (evidenced from LCMS), ice cooled water (5 mL) was added to thereaction mixture and extracted with ethyl acetate (3×30 mL). Organicportion was separated, dried over anhydrous sodium sulfate andconcentrated. Crude thus obtained washed with diethyl ether to get thepure compound1-[(4-methoxyphenyl)methyl]-6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]benzo[cd]indol-2-one8 (320 mg, 519.52 umol, 87.28% yield) as yellow solid which stored in around bottomed flask at ambient temperature. LC MS: ES+ 604.3. Step 5:Synthesis of6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]-1H-benzo[cd]indol-2-one(9): To the stirred solution of1-[(4-methoxyphenyl)methyl]-6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]benzo[cd]indol-2-one8 (320 mg, 530.12 umol) in TFA (2.0 mL), trifluoromethanesulfonic acid(477.36 mg, 3.18 mmol, 279.16 uL) was added at room temperature andstirred for 12 hours at same temp. After complete consumption ofstarting material (evidenced from TLC), RM was quenched with saturatedsodium bicarbonate solution (maintain pH-8) and extracted with ethylacetate (40 mL). Organic portion was separated, dried over sodiumsulfate and concentrated under reduced pressure. The crude thus obtainedwas purified by flash chromatography (100-200 silica; 0-100% Ethylacetate in Hexane) to afford6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]-1H-benzo[cd]indol-2-one9 (234 mg, 479.15 umol, 90.38% yield) which kept in a round bottomedflask at ambient temperature. LC MS: ES+ 484.3.

Step 6: Synthesis of3-[6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a ice cooled solution of6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]-1H-benzo[cd]indol-2-one9 (122 mg, 252.33 umol) in dry THF (10.0 mL) Sodium hydride 60%dispersion in mineral oil (55.57 mg, 2.42 mmol) portion wise,maintaining the temp <5° C. Once the addition is over, the resultantmixture was stirred for 15 minutes at RT. Then the reaction mixture wasagain cooled to 0° C. and 3-bromopiperidine-2,6-dione 10 (242.25 mg,1.26 mmol) was added to it portion wise. After complete addition,resulting solution was heated at 70° C. for 1 hour. After completion(evidenced from TLC), the reaction mixture was again cooled to 0° C. andquenched with ice cooled water (40 mL). Aqueous part was extracted withethyl acetate (3×50 mL). Combined extracts was dried over anhydroussodium sulfate and concentrated under reduced pressure. Crude mass waspurified by flash chromatography (silica, gradient: 2.5% MeOH in DCM) toafford3-[6-[[4-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 127 (48.0 mg, 80.01 umol, 31.71% yield, 99.11% purity) asyellow solid which was stored in a round bottomed flask at 5° C. insidea refrigerator. ¹H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.42 (d,J=8.2 Hz, 1H), 8.13 (d, J=7.12 Hz, 1H), 8.06 (s, 1H), 7.89 (t, J=7.12Hz, 1H), 7.56 (d, J=7.08 Hz, 1H), 7.17 (d, J=7.4 Hz, 1H), 5.99 (s, 2H),5.47-5.45 (m, 1H), 3.76-3.73 (m, 2H), 2.98-2.92 (m, 1H), 2.76-2.50 (m,4H), 2.10-1.99 (m, 3H), 1.53 (br m, 2H), 1.25-1.14 (m, 7H); LC MS: ES+593.4.

Example 46. Synthesis of4-[4-[[1-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile(Compound 128)

Step 1: Synthesis of tert-butyl4-(4-cyano-2-fluoro-phenyl)piperazine-1-carboxylate (3): To a stirredsolution of 3,4-difluorobenzonitrile (1) (13 g, 93.46 mmol) in DMSO (80mL), Potassium carbonate (19.37 g, 140.18 mmol, 8.46 mL) and tert-butylpiperazine-1-carboxylate (2) (19.15 g, 102.80 mmol) were added and theresultant reaction mixture was heated at 100° C. for 16 hours. Aftercompletion (monitored by TLC), the reaction mixture was allowed to cooland water (500 ml) was added to it. The solid that formed was filteredoff, washed with water, and dried under vacuum to obtain tert-butyl4-(4-cyano-2-fluoro-phenyl)piperazine-1-carboxylate (3) (20 g, 66%yield) as a white solid. LC MS: ES+ 306.2.

Step 2: Synthesis of 3-fluoro-4-piperazin-1-yl-benzonitrileHydrochloride salt (4): To a stirred solution of tert-butyl4-(4-cyano-2-fluoro-phenyl)piperazine-1-carboxylate (3) (20 g, 65.50mmol) in Dioxane (15 mL) was added Dioxane-HCl (65.50 mmol, 50 mL) andthe reaction mixture was stirred at RT for 3 hours. All the volatileswere removed under reduced pressure. The solid obtained was trituratedwith ether to afford 3-fluoro-4-piperazin-1-yl-benzonitrile;hydrochloride (4) (17 g, 88% yield) as a white solid. LC MS: ES+ 206.4.

Step 3: Synthesis of3-fluoro-4-[4-(1H-pyrazol-4-ylmethyl)piperazin-1-yl]benzonitrile (6): Toa stirred solution of 3-fluoro-4-piperazin-1-yl-benzonitrile;hydrochloride (4) (2 g, 8.27 mmol) in Methanol (20 mL) was added Aceticacid (496.93 mg, 8.27 mmol, 473.27 uL) and the reaction was stirred atRT for 10 min. Then 1H-pyrazole-4-carbaldehyde (5) (1.19 g, 12.41 mmol)followed by Sodium cyanoborohydride (780.03 mg, 12.41 mmol) and Triethylamine (1.26 g, 12.41 mmol, 1.73 mL) were added and the reaction mixturewas stirred at RT for 16 hr. After completion of the reaction (monitoredby TLC) the reaction mixture was diluted with DCM and washed with water,sodium bicarbonate and brine, dried over sodium sulfate and concentratedunder reduced pressure. The crude was purified by combiflash column(Gradient 0-3% MeOH in DCM) to afford3-fluoro-4-[4-(1H-pyrazol-4-ylmethyl)piperazin-1-yl]benzonitrile (6) (1g, 40.66% yield) as yellow gum. LC MS: ES+ 286.3.

Step 4: Synthesis of3-fluoro-4-[4-[[1-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile(8): To a stirred solution of3-fluoro-4-[4-(1H-pyrazol-4-ylmethyl)piperazin-1-yl]benzonitrile (6) (2g, 7.01 mmol) in DMF (40 mL) were added Cesium carbonate (5.71 g, 17.52mmol) and6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (7)(3.55 g, 10.51 mmol) and the resultant reaction mixture was heated at90° C. for 16 h. After completion of the reaction (monitored by TLC) thereaction mixture was diluted with cooled water extracted with ethylacetate (Twice). The combined organic layer was further washed withwater and saturated brine solution, dried over sodium sulphate andconcentrated under reduced pressure. The crud thus obtained was purifiedby combiflash Column (Gradient 0-1% MeOH in DCM) to afford3-fluoro-4-[4-[[1-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile(8) (2.6 g, 56.90% yield) as light yellow solid. LC MS ES+ 587.4.

Step 5: Synthesis of3-fluoro-4-[4-[1-[(2-oxo-1H-benzo[cd]indol-5-yl)methyl]pyrazol-4-yl]piperazin-1-yl]benzonitrile(9): To a stirred solution of3-fluoro-4-[4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-5-yl]methyl]pyrazol-4-yl]piperazin-1-yl]benzonitrile(8) (2.5 g, 4.37 mmol) in TFA (20 mL) was added trifluoromethanesulfonicacid (6.55 g, 43.66 mmol, 3.83 mL) and the resultant reaction mixturewas stirred at room temperature for 16 h. After completion of thereaction (monitored by TLC) the reaction mass was concentrated underreduced pressure. The crude was then basified with saturated bicarbonatesolution and extracted with ethyl acetate. The organic layer was furtherwashed with water and brine, dried over sodium sulphate and concentratedunder reduced pressure. The crude thus obtained was purified bycombiflash column (3% MeOH in DCM) to afford3-fluoro-4-[4-[1-[(2-oxo-1H-benzo[cd]indol-5-yl)methyl]pyrazol-4-yl]piperazin-1-yl]benzonitrile(9) (1.4 g, 67.33% yield) as light yellow solid. LC MS ES+ 467.3.

Step 6: Synthesis of4-[4-[[1-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile:To a cooled solution of3-fluoro-4-[4-[[1-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-4-yl]methyl]piperazin-1-yl]benzonitrile(9) (800 mg, 1.71 mmol) in dry THF (7 mL), Sodium hydride (60%dispersion in mineral oil) (394.25 mg, 17.15 mmol) was added portionwise, maintaining the temp <5° C. Once the addition is over, theresultant mixture was stirred for 15 minutes at RT. Then the reactionmixture was again cooled to 0° C. and 3-bromopiperidine-2,6-dione (10)(1.65 g, 8.57 mmol) was added to it portion wise. After completeaddition, resulting solution was heated at 70° C. 1 hour. Aftercompletion (evidenced from TLC), the reaction mixture was cooled to 0°C. and quenched with the addition of ice cooled water. Aqueous part wasextracted with ethyl acetate (Twice). Combined organics was separated,dried over sodium sulphate and concentrated under reduced pressure.Crude mass was purified by column chromatography (silica, gradient:30-100% EtOAc in DCM) to afford4-[4-[[1-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluoro-benzonitrileCompound 128 (600 mg, 60.5% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.40 (d, J=8.16 Hz, 1H), 8.10 (d, J=6.88 Hz,1H), 7.85 (t, J=7.66 Hz, 1H), 7.75 (s, 1H), 7.67 (m, 1H), 7.54 (d,J=8.36 Hz, 1H), 7.48 (d, J=9.32 Hz, 1H), 7.35 (s, 1H), 7.14-7.08 (m,2H), 5.72 (s, 2H), 5.47-5.44 (m, 1H), 3.36 (s, 2H), 3.13 (br s, 4H),2.98-2.91 (m, 1H), 2.80-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.45 (br s,4H), 2.09-2.07 (m, 1H); LC MS: ES+ 578.2.

Step 7: Chiral separation: Synthesis of4-[4-[[1-[[1-[-2,6-dioxo-3-piperidyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile(Compound 129) and4-[4-[[1-[[1-[2,6-dioxo-3-piperidyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile(Compound 130): Using a C-Amylose A (250×30 mm) 5μ column passingthrough a mobile phase of 45% CO₂+55% isopropyl alcohol at a flow rateof 30 mL/min, a temperature of 35 C and ABPR of 120 bar to afford4-[4-[[1-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile(11) (600 mg, 1.04 mmol) was separated into enantiomers by chiral SFCmethod to afford4-[4-[[1-[[1-[2,6-dioxo-3-piperidyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluoro-benzonitrileCompound 129) (220 mg, % ee 98.1)) as first eluting peak from column ¹HNMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.40 (d, J=8.16 Hz, 1H), 8.10(d, J=6.88 Hz, 1H), 7.85 (t, J=7.66 Hz, 1H), 7.75 (s, 1H), 7.67 (m, 1H),7.54 (d, J=8.36 Hz, 1H), 7.48 (d, J=9.32 Hz, 1H), 7.35 (s, 1H),7.14-7.08 (m, 2H), 5.72 (s, 2H), 5.45 (dd, J=12.8, 5.12 Hz, 1H), 3.35(s, 2H), 3.13 (br s, 4H), 2.98-2.91 (m, 1H), 2.80-2.73 (m, 1H),2.67-2.63 (m, 1H), 2.45 (br s, 4H), 2.09-2.07 (m, 1H); LC MS: ES+ 578.6;and4-[4-[[1-[[1-[2,6-dioxo-3-piperidyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-4-yl]methyl]piperazin-1-yl]-3-fluoro-benzonitrileCompound 130 (215 mg, % ee 100) as second eluting peak from column asyellow solids, ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.40 (d,J=8.16 Hz, 1H), 8.10 (d, J=6.88 Hz, 1H), 7.85 (t, J=7.66 Hz, 1H), 7.75(s, 1H), 7.67 (m, 1H), 7.54 (d, J=8.36 Hz, 1H), 7.48 (d, J=9.32 Hz, 1H),7.35 (s, 1H), 7.14-7.08 (m, 2H), 5.72 (s, 2H), 5.45 (dd, J=12.8, 5.12Hz, 1H), 3.35 (s, 2H), 3.13 (br s, 4H), 2.98-2.91 (m, 1H), 2.80-2.73 (m,1H), 2.67-2.63 (m, 1H), 2.45 (br s, 4H), 2.09-2.07 (m, 1H); LC MS: ES+578.6.

Example 47. Synthesis of4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octan-7-yl]-3-fluoro-benz° nitrite (Compound 131)

Step 1: Synthesis of tert-butyl4-[[4-(chloromethyl)phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate(3): To a stirred solution of tert-butyl4,7-diazaspiro[2.5]octane-7-carboxylate 1 (550 mg, 2.59 mmol) in drygrade acetone (5.0 mL) was added Potassium carbonate, anhydrous, 99%(1.07 g, 7.77 mmol, 469.09 uL) at RT and the resultant reaction mixturewas heated at 50° C. for 20 minutes. 1,4-bis(chloromethyl)benzene 2(453.53 mg, 2.59 mmol, 319.39 uL) was then added to the reaction mixtureand heating was continued for 3 hours. After completion of reaction(monitored by TLC and LCMS), volatiles were removed under vacuum and thesolid thus obtained was taken in Ethyl acetate (50 mL), washed withwater (3×20 ml), Brine (2×15 mL), dried over anhydrous sodium sulfateand concentrated under reduced pressure. Crude mass was purified bycolumn chromatography (silica, gradient: 10-50% Ethyl acetate in Hexane)to afford tert-butyl4-[[4-(chloromethyl)phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate3 (300 mg, 795.14 umol, 30.69% yield) as colorless sticky solid whichwas stored in a round bottomed flask at 5° C. inside a refrigerator. LCMS: ES+ 351.4.

Step 2: Synthesis of tert-butyl4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate(5): To a well degassed solution of -butyl4-[[4-(chloromethyl)phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate3 (700 mg, 1.99 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one4 (1.18 g, 3.99 mmol) in Ethanol (2 mL)-Toluene (4 mL), Potassiumphosphate tribasic, anhydrous, (1.27 g, 5.98 mmol) was added followed bythe addition of Tri-o-Tolyl phosphine (121.44 mg, 398.99 umol) andPd₂(dba)₃ (182.68 mg, 199.50 umol). The resulting mixture was thenheated at 90° C. for 12 hours. After completion of reaction (asmonitored by LCMS), the reaction mixture was filtered through a bed ofcelite, washed with ethyl acetate (30 mL). The combined filtrate wasthen washed with water (3×20 mL) and brine (2×15 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Crudemass was purified by column chromatography (silica, gradient: 0-20%Ethyl acetate in DCM) to obtain tert-butyl4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate5 (450 mg, 809.55 umol, 40.58% yield, 87% purity) as yellow solid whichwas stored in a Tarson plastic bottle at ambient temperature. LC MS: ES+484.4.

Step 3: Synthesis tert-butyl4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate(7): To a ice cooled solution tert-butyl4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate5 (425 mg, 878.83 umol) in dry THF (10 mL), Sodium hydride (60%dispersion in mineral oil) (202.04 mg, 8.42 mmol) was added portionwise, maintaining the temp <5° C. Once the addition is over, theresultant mixture was stirred for 15 minutes at RT. Then the reactionmixture was again cooled to 0° C. and 3-bromopiperidine-2,6-dione 6(843.72 mg, 4.39 mmol) was added to it portion wise. After completeaddition, resulting solution was heated at 70° C. for 1 hour. Aftercompletion (evidenced from TLC), the reaction mixture was again cooledto 0° C. and quenched with ice cooled water (40 mL). Aqueous part wasextracted with ethyl acetate (3×50 mL). Combined extracts was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Crudemass was purified by PREP-TLC (50% ethyl acetate in DCM as eluent) toafford tert-butyl4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate7 (320 mg, 414.33 umol, 47.15% yield) as yellow solid which was storedin a round bottomed flask at 5° C. inside a refrigerator. LC MS: ES+595.7.

Step 4: Synthesis of3-[6-[[4-(4,7-diazaspiro[2.5]octan-4-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione;hydrochloride (8): To the stirred solution of tert-butyl4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate7 (200 mg, 336.30 umol) in dry Dioxane (5.0 mL), Dioxane-HCl (336.30umol, 5.0 mL) was added at 0° C. and stirred for 2 at rt. Aftercompletion of reaction (evidenced from LC MS), volatiles were removedunder reduced pressure to afford crude3-[4-[[4-(4,7-diazaspiro[2.5]octan-4-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione;hydrochloride 8 (150 mg, 198.24 umol, 58.95% yield, 75% purity) asyellow solid. LC MS: ES+ 495.4.

Step 5: Synthesis of4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octan-7-yl]-3-fluoro-benzonitrile:To the well degassed solution of3-[6-[[4-(4,7-diazaspiro[2.5]octan-4-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione;hydrochloride 8 (175 mg, 329.54 umol) in NMP (2.0 mL),N,N-Diisopropylethylamine (255.54 mg, 1.98 mmol, 344.39 uL) was addedfollowed by 3,4-difluorobenzonitrile (68.76 mg, 494.31 umol). Resultingsolution was then heated at 110° C. for 12 hr in sealed tube. Aftercompletion of reaction as evidenced from LC MS, reaction mixture wascooled to RT and ice cooled water (5 mL) was added to it. Aqueous partwas extracted with ethyl acetate (3×30 mL). Organic phase was separated,dried over sodium sulfate and concentrated. Crude residue was purifiedby PREP TLC (40% Ethyl acetate in DCM) to afford4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octan-7-yl]-3-fluoro-benzonitrileCompound 131 (40.0 mg, 64.57 umol, 19.60% yield) as yellow solid whichwas stored in a round bottomed flask at 5° C. inside a refrigerator. ¹HNMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.31 (d, J=8.24 Hz, 1H), 8.07(d, J=6.96 Hz, 1H), 7.80 (t, J=7.36 Hz, 1H), 7.65 (d, J=12.88 Hz, 1H),7.54 (d, J=7.48 Hz, 1H), 7.39 (d, J=7.48 Hz, 1H), 7.23-7.16 (m, 4H),7.12-7.08 (m, 2H), 5.44-5.42 (m, 1H), 4.36 (s, 2H), 3.76 (s, 2H), 3.18(m, 2H), 3.07 (s, 2H), 2.98-2.91 (m, 1H), 2.77-2.74 (m, 3H), 2.66-2.62(m, 1H), 2.07 (br m, 1H), 0.64 (m, 2H), 0.54 (m, 2H); LC MS: ES+ 614.2.

Example 48. Synthesis ofN-tert-butyl-4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-N-methyl-piperidine-1-carboxamide(Compound 132)

Step 1: Synthesis ofN-tert-butyl-4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-N-methyl-piperidine-1-carboxamide:To the stirred solution of bis(trichloromethyl) carbonate (75.07 mg,252.97 umol) in dry grade DCM (20 mL), solution of3-[2-oxo-6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione1 (249.32 mg, 562.16 umol) in dry DCM (20 mL) was added drop wise at 0°C. followed by the addition of solution of N,N Di iosopropyl ethyl amine(163.48 mg, 1.26 mmol, 220.32 uL) in DCM (5 mL) under inert atmosphere.After complete addition, reaction mixture was kept on stirring at rt for30 minutes at rt. Then solution of N,2-dimethylpropan-2-amine (49 mg,562.16 umol, 67.40 uL) in DCM (20 mL) was added to the reaction mixtureat rt and stirred further for 12 hours at same temperature. Aftercompletion of reaction (evidenced from LC MS), reaction mixture waswashed with water (2×20 mL)/brine (20 mL). Organic part was separated,dried over anhydrous sodium sulfate and concentrated under reducedpressure. Crude thus obtained was purified by Preparative TLC Plate(eluting with 60% Ethyl acetate in DCM) to affordN-tert-butyl-4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-N-methyl-piperidine-1-carboxamideCompound 132 (20 mg, 34.13 umol, 6.07% yield, 95% purity) as yellowsolid. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.28 Hz,1H), 8.08 (d, J=6.8 Hz, 1H), 7.82 (t, J=7.28 Hz, 1H), 7.35 (d, J=7.2 Hz,1H), 7.31 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=7.16 Hz, 1H),4.18 (br s, 3H), 3.67 (m, 2H), 2.94-2.90 (m, 1H), 2.80-2.77 (m, 3H),2.62 (br s, 4H), 1.90-1.87 (m, 1H), 1.74-1.66 (m, 4H), 1.22 (s, 9H); LCMS: ES+ 557.3.

Example 49. Synthesis of tert-butyl4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate(Compound 133)

Step 1: Synthesis of3-amino-1-(1-benzyl-4-methyl-4-piperidyl)pyrazole-4-carboxylate (3):Mixture solution of (1-benzyl-4-methyl-4-piperidyl)hydrazine 1 (2 g,9.12 mmol) and Ethyl (ethoxymethylene)cyanoacetate 2 (1.54 g, 9.12 mmol)in Methanol (20 mL) was heated at 80° C. for 12 hours. After completionof reaction (evidenced from TLC), solvent was evaporated and crude thusobtained was purified by column chromatography (silica, gradient: 0-5%DCM in MeOH) to afford ethyl3-amino-1-(1-benzyl-4-methyl-4-piperidyl)pyrazole-4-carboxylate 3 (1.5g, 3.94 mmol, 43.23% yield, 90% purity) as yellow gummy solid which wasstored in a round bottomed flask at 5° C. inside a refrigerator. LC MS:ES+ 343.0.

Step 2: Synthesis of1-(1-benzyl-4-methyl-4-piperidyl)-3-chloro-pyrazole-4-carboxylate (4):To dry grade Acetonitrile (20 mL) was added tert-Butyl nitrite, tech.90% (677.56 mg, 6.57 mmol, 781.50 uL) followed by CuCl (650.49 mg, 6.57mmol) and the reaction mixture was then slowly heated up to 65° C. underN₂ atmosphere. At this temperature, ethyl3-amino-1-(1-benzyl-4-methyl-4-piperidyl)pyrazole-4-carboxylate 3 (1.5g, 4.38 mmol) dissolved in dry Acetonitrile (20 mL) was slowly added tothe reaction mixture. The reaction mixture was stirred at thistemperature for 0.5 hour. Reaction mixture was then cooled to roomtemperature, water (15 mL) was added and extracted with EtOAc (2×35 mL).The organic part was then washed with saturated sodium bicarbonatesolution/brine solution (30 mL), separated, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. Crude thus obtained wasthen purified by column chromatography eluting (silica, gradient: 0-10%EtOAc in Hexane) to afford ethyl1-(1-benzyl-4-methyl-4-piperidyl)-3-chloro-pyrazole-4-carboxylate 4 (650mg, 1.62 mmol, 36.91% yield) as brown gummy solid. LC MS: ES+ 362.0.

Step 3: Synthesis of tert-butyl4-(3-chloro-4-ethoxycarbonyl-pyrazol-1-yl)-4-methyl-piperidine-1-carboxylate(5): To the stirred solution of ethyl1-(1-benzyl-4-methyl-4-piperidyl)-3-chloro-pyrazole-4-carboxylate 4 (1.3g, 3.59 mmol) in DCM (20 mL), 1-Chloroethyl chloroformate (513.62 mg,3.59 mmol, 392.07 uL) was added at 0° C. and resulting solution washeated at 100° C. for 90 minutes. After complete conversion as monitoredby TLC, solvent was evaporated and re dissolved in MeOH (20 mL). RM wasthen further heated at 100° C. for 1 hour. After complete consumption ofintermediate as evidenced from TLC, Methanol was evaporated and crudewas re-dissolved in DCM (20 mL). To this solution, triethylamine (363.52mg, 3.59 mmol, 500.72 uL) was added at 0° C. to maintain the pH 8,followed by the addition of tert-butoxycarbonyl tert-butyl carbonate(784.05 mg, 3.59 mmol, 824.45 uL). Resulting reaction mixture wasstirred at room temperature for further 16 hours. After completion ofreaction (monitored by TLC), reaction mixture was diluted with ethylacetate (80 mL) and washed with water (25 mL). Combined organic layerwas separated, dried over anhydrous sodium sulfate and concentrated.Crude residue was purified by column chromatography (silica, gradient:0-10% EtOAc in Hexane) to afford tert-butyl4-(3-chloro-4-ethoxycarbonyl-pyrazol-1-yl)-4-methyl-piperidine-1-carboxylate5 (750 mg, 1.82 mmol, 50.53% yield) as light brown sticky solid whichwas stored in a round bottomed flask at ambient temperature. LC MS: ES+372.33.

Step 4: Synthesis of tert-butyl4-[3-chloro-4-(hydroxymethyl)pyrazol-1-yl]-4-methyl-piperidine-1-carboxylate(6): To the stirred solution of tert-butyl4-(3-chloro-4-ethoxycarbonyl-pyrazol-1-yl)-4-methyl-piperidine-1-carboxylate5 (750 mg, 2.02 mmol) in THF (20.0 mL), Di-iso Butyl AluminiumHydride(25% intoluene) (1.43 g, 10.08 mmol, 1.80 mL) (60.0 ml) was addeddrop wise at −78° C. for 1.5 hour under N₂ atmosphere. After completeconsumption, as evidenced from TLC, reaction mass was diluted with ethylacetate (60 mL) and quenched with water (30 mL). Organic phase wasseparated, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford tert-butyl4-[3-chloro-4-(hydroxymethyl)pyrazol-1-yl]-4-methyl-piperidine—carboxylate6 (560 mg, 1.53 mmol, 75.76% yield, 90% purity). The crude was directlyused for next step without any purification. LC MS: ES+ 330.3.

Step 5: Synthesis of tert-butyl4-(3-chloro-4-formyl-pyrazol-1-yl)-4-methyl-piperidine-1-carboxylate(7): To a stirred solution of tert-butyl4-[3-chloro-4-(hydroxymethyl)pyrazol-1-yl]-6 (550 mg, 1.67 mmol) inAcetonitrile (5 mL), was added activated MnO₂ (724.89 mg, 8.34 mmol andstirred at room temperature for 24 hours. After completion of thereaction (monitored by TLC and LC MS), reaction mass was filteredthrough bed of celite and the filtrate was concentrated under reducedpressure. Crude mass was purified by flash chromatography (0-50% EtOAcin Hexane as eluent) to get the pure compound tert-butyl4-(3-chloro-4-formyl-pyrazol-1-yl)-4-methyl-piperidine—carboxylate 7(360 mg, 988.39 umol, 59.27% yield, 90% purity) as light yellow stickysolid and stored in a round bottomed flask at 5° C. inside arefrigerator. LC MS: ES+ (M-100) 228.2 (M-100).

Step 6: Synthesis of tert-butyl4-[3-chloro-4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methyl-piperidine-1-carboxylate(9): To the stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 8 (270mg, 1.09 mmol) in dry grade THF (5.0 mL), was added Phenyllithium, 1.8Min di-n-butyl ether (91.47 mg, 1.09 mmol, 112.93 uL) at −78° C. under N2atmosphere and the reaction was stirred at the same temperature for 30minutes followed by the addition of butyllithium (76.69 mg, 1.20 mmol)at −78° C. and after the addition was complete, the temperature wasallowed to increase to −40° C. and stirred at the same temperature for30 minutes. After getting the dessbormo spot in TLC (30% ethyl acetatein Hexane) solution of tert-butyl4-(3-chloro-4-formyl-pyrazol-1-yl)-4-methyl-piperidine-1-carboxylate 7(356.78 mg, 1.09 mmol) in dry THF (5.0 mL) was added at −78° C. andresulting solution was allowed to warm to room temperature and stirringwas continued for 16 hours. After completion of reaction (evidenced fromTLC and LC MS), the reaction mixture was quenched with saturatedammonium chloride solution and extracted with with ethyl acetate (2×40mL). Organic phase was washed with water (2×20 mL) and separated, driedover anhydrous sodium sulphate and evaporated under reduced pressure toobtain the crude compound which was purified by flash chromatography(silica, gradient: 0-5% MeOH in DCM) to afford tert-butyl4-[3-chloro-4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methyl-piperidine-1-carboxylate9 (123 mg, 197.99 umol, 18.19% yield, 80% purity) as brown solid. LC MS:ES+ 479.4 (m-16).

Step 7: Synthesis of[4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methyl-1-piperidyl]2,2,2-trifluoroacetate(10): To the stirred solution of tert-butyl4-[3-chloro-4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methyl-piperidine-1-carboxylate9 (123 mg, 247.49 umol) in DCE (2.0 mL) was added triethylsilane (115.11mg, 989.97 umol, 158.12 uL) and Trifluoroacetic acid, 99% (225.75 mg,1.98 mmol, 152.54 uL) at rt. Resulting reaction mixture was heated at70° C. under microwave condition for 30 mins. After completion ofreaction (monitored by TLC and LCMS), volatiles were removed to affordcrude[4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methyl-1-piperidyl]2,2,2-trifluoroacetate10 (110 mg, 122.25 umol, 49.39% yield) which was used in the next stepwithout purification. LCMS: ES+ 381.2.

Step 8: Synthesis of6-[[3-chloro-1-[4-methyl-1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(11): To the stirred solution of6-[[3-chloro-1-(4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one10 (120 mg, 315.07 umol) in DMF (5.0 mL), HATU (179.70 mg, 472.60 umol)was added at 0° C. followed by the mixture solution of1-methylcyclobutanecarboxylic acid (89.91 mg, 787.67 umol) andN,N-Diisopropylethylamine (203.60 mg, 1.58 mmol, 274.39 uL) under N₂atmosphere. Resulting solution was stirred for 12 hours at sametemperature. After completion of reaction (monitored by LC MS, crude LCMS showed di amidation mass), RM was quenched with the addition of icecooled water (5 mL). Aqueous part was extracted with ethyl acetate (3×30mL). Organic portion was separated, dried over anhydrous sodium sulfateand concentrated. Crude residue was then re-dissolved in Methanol (10mL) and stirred for 30 minutes in presence of LiOH (1.5 eq). Aftercomplete consumption of Diamide, solvent was evaporated and re-dissolvedin ethyl acetate (30 ml). Organic portion was washed with 1 N HCl (20Ml) and separated, dried over sodium sulfate, concentrated under reducedpressure to obtain crude6-[[3-chloro-1-[4-methyl-1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1Hbenzo[cd]indol-2-one 11 (90 mg, 177.36 umol, 56.29% yield) as browngummy solid which was sufficiently pure to use in the next step. LC MS:ES+ 477.39 Step 9: Synthesis of tert-butyl4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylate:To a ice cooled solution6-[[3-chloro-1-[4-methyl-1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one11 (90 mg, 188.68 umol) in dry THF (5 mL), Sodium hydride (60%dispersion in mineral oil) (43.38 mg, 1.89 mmol) was added portion wise,maintaining the temp <5° C. Once the addition is over, the resultantmixture was stirred for 15 minutes at room temperature. Then thereaction mixture was again cooled to 0° C. and3-bromopiperidine-2,6-dione 12 (181.14 mg, 943.40 umol) was added to itportion wise. After complete addition, resulting solution was heated at70° C. for 2 hour. After completion (evidenced from TLC), the reactionmixture was again cooled to 0° C. and quenched with ice cooled water (40mL). Aqueous part was extracted with ethyl acetate (2×20 mL). Combinedextracts was dried over anhydrous sodium sulfate and concentrated underreduced pressure. Crude mass was purified by Preparative TLC plate (2.5%MeOH in DCM as eluent) to afford tert-butyl4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-7-carboxylateCompound 133 (320 mg, 414.33 umol, 47.15% yield) as yellow solid whichwas stored in a round bottomed flask at 5° C. inside a refrigerator. 1HNMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.10(d, J=7.0 Hz, 1H), 7.86 (t, J=7.48 Hz, 1H), 7.45 (s, 1H), 7.25 (d,J=7.28 Hz, 1H), 7.07 (d, J=7.16 Hz, 1H), 5.44 (dd, J=12.52, 5.4 Hz, 1H),4.16 (s, 2H), 3.80 (br m, 1H), 3.33 (br m, 2H), 3.15-3.06 (m, 2H),2.98-2.91 (m, 1H), 2.78-2.62 (m, 4H), 2.37 (br, 2H), 2.10-2.07 (br m,1H), 1.90-1.77 (m, 4H), 1.60 (m, 1H), 1.52 (s, 3H), 1.31 (s, 3H); LC MS:ES+ 588.2.

Example 50. Synthesis of3-[6-[[4-[4-(2-fluorophenyl)piperazine-1-carbonyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 134)

Step 1: Synthesis of[4-(chloromethyl)phenyl]-[4-(2-fluorophenyl)piperazin-1-yl]methanone(3): To the stirred solution of 1-(2-fluorophenyl)piperazine 2 (1.0 g,5.55 mmol) in dry grade DCM (20 mL), Triethylamine, 99% (1.68 g, 16.65mmol, 2.32 mL) was added at 0° C. followed by drop wise addition of4-(chloromethyl)benzoyl chloride 1 (1.26 g, 6.66 mmol). After completeaddition, reaction mixture was stirred for 5 hours at room temperature.Reaction mixture was diluted with DCM (30 mL) and quenched withsaturated sodium bicarbonate solution. Organic phase was washed withwater (20 mL)/brine (20 mL) and separated, dried over anhydrous sodiumsulfate and concentrated. Crude thus obtained was purified by columnchromatography (silica, gradient: 0-30% Ethyl acetate in Hexane) toafford[4-(chloromethyl)phenyl]-[4-(2-fluorophenyl)piperazin-1-yl]methanone 3(671 mg, 1.63 mmol, 29.43% yield, 81% purity) as a white solid. LC MS:ES+ 333.3.

Step 2: Synthesis of6-[[4-[4-(2-fluorophenyl)piperazine-1-carbonyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(5): To a well degassed solution of[4-(chloromethyl)phenyl]-[4-(2-fluorophenyl)piperazin-1-yl]methanone 3(650 mg, 1.95 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one4 (1.44 g, 4.88 mmol) in Ethanol (4 mL)-Toluene (8 mL), Potassiumphosphate tribasic, anhydrous, (1.24 g, 5.86 mmol) was added followed bythe addition of Tri-o-Tolyl phosphine (118.89 mg, 390.63 umol) andPd₂(dba)₃ (178.85 mg, 195.31 umol). The resulting mixture was thenheated at 90° C. for 12 hours. After completion of reaction (asmonitored by LCMS), the reaction mixture was filtered through a bed ofcelite, washed with Ethyl acetate (30 mL). The combined filtrate wasthen washed with water (3×30 mL) and brine (2×20 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Crudemass was purified by flash chromatography (gradient: 0-20% Ethyl acetatein DCM) to obtain6-[[4-[4-(2-fluorophenyl)piperazine-1-carbonyl]phenyl]methyl]-1H-benzo[cd]indol-2-one5 (500 mg, 966.67 umol, 49.49% yield) as yellow solid which was storedin a Tarson plastic bottle at ambient temperature. LC MS: ES+ 466.2.

Step 3: Synthesis of3-[6-[[4-[4-(2-fluorophenyl)piperazine-1-carbonyl]phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione: To a ice cooled solution6-[[4-[4-(2-fluorophenyl)piperazine-1-carbonyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(130 mg, 279.26 umol) 5 in dry THF (8 mL), Sodium hydride (60%dispersion in mineral oil) (64.20 mg, 2.79 mmol) was added portion wise,maintaining the temp <5° C. Once the addition is over, the resultantmixture was stirred for 15 minutes at room temperature. Then thereaction mixture was again cooled to 0° C. and3-bromopiperidine-2,6-dione 6 (268.10 mg, 1.40 mmol) was added to itportion wise. After complete addition, resulting solution was heated at70° C. for 1.5 hour. After completion (evidenced from TLC), the reactionmixture was again cooled to 0° C. and quenched with ice cooled water (20mL). Aqueous part was extracted with ethyl acetate (2×20 mL). Combinedextracts was dried over anhydrous sodium sulfate and concentrated underreduced pressure. Crude mass was then purified by Preparative TLC plate(2.5% MeOH in DCM as eluent) to afford3-[6-[[4-[4-(2-fluorophenyl)piperazine-1-carbonyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 134 (42 mg, 70.24 umol, 25.15% yield) as yellow solid which wasstored in a round bottomed flask at 5° C. inside a refrigerator. ¹H NMR(400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.35 (d, J=8.04 Hz, 1H), 8.08 (d,J=6.92 Hz, 1H), 7.82 (t, J=7.36 Hz, 1H), 7.45 (d, J=7.28 Hz, 1H),7.36-7.35 (m, 4H), 7.13-7.07 (m, 3H), 7.04-7.0 (m, 2H), 5.44 (dd,J=12.84 Hz, 1H), 4.45 (s, 2H), 3.71 (br m, 2H), 3.46 (br m, 2H), 2.96(br m, 5H), 2.76-2.63 (m, 2H), 2.08 (m, 1H); LC MS: ES+ 577.2.

Example 51. Synthesis of3-[6-[[4-[[7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 135)

Step 1: Synthesis of tert-butyl7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (3): To awell degassed solution of 1-fluoro-2-iodo-benzene 1 (2.09 g, 9.42 mmol,1.10 mL) intoluene (60 mL), tert-butyl4,7-diazaspiro[2.5]octane-4-carboxylate 2 (2.0 g, 9.42 mmol) and sodiumtert-butoxide (1.81 g, 18.84 mmol) were added followed by the additionof Pd₂(dba)₃ (172.54 mg, 188.42 umol),2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene (586.63 mg, 942.12 umol).The resulting mixture was then heated at 100° C. for 12 hours. Aftercompletion of reaction (as monitored by LCMS), the reaction mixture wasfiltered through a bed of celite, washed with ethyl acetate (30 mL). Thecombined filtrate was then washed with water (3×50 mL) and brine (20mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure. Crude mass was purified by flash chromatography (gradient:0-10% Ethyl acetate in Hexane) to afford tert-butyl7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate 3 (810 mg,2.56 mmol, 27.22% yield) as yellow solid which was stored in a Tarsonplastic bottle at ambient temperature. LC MS: ES+ 307.16.

Step 2: Synthesis of 7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane;hydrochloride (4): To a stirred solution of tert-butyl7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate 3 (805 mg,2.63 mmol) in Dioxane (10 mL), Dioxane-HCl (2.63 mmol, 10.0 mL) wasadded drop wise at 0° C. and stirred the reaction at room temperaturefor 16 hours. After completion of reaction (evidenced from LC MS),volatiles were removed. Solid reaction mass was triturated with diethylether to afford 7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane;hydrochloride 4 (630 mg, 2.17 mmol, 82.58% yield) and the crude wasdirectly used for the next step without any further purification.

Step 3: Synthesis of4-[[4-(chloromethyl)phenyl]methyl]-7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane(6): To a stirred solution 7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane;hydrochloride 4 (630 mg, 2.60 mmol) in dry grade acetone (5.0 mL) wasadded DIPEA (335.45 mg, 2.60 mmol, 452.09 uL) was added followed byPotassium carbonate, anhydrous, 99% (1.08 g, 7.79 mmol, 469.96 uL) at RTand the resultant reaction mixture was heated at 60° C. for 20 minutes.1,4-bis(chloromethyl)benzene 5 (454.37 mg, 2.60 mmol, 319.98 uL) wasthen added to the reaction mixture and heating was continued for 3hours. After completion of reaction (monitored by TLC and LCMS),volatiles were removed under vacuum and the solid thus obtained wastaken in Ethyl acetate (50 mL), washed with water (3×25 ml) and Brine(2×15 mL), dried over anhydrous sodium sulfate and concentrated underreduced pressure. Crude mass was purified by column chromatography(silica, gradient: 10-30% Ethyl acetate in Hexane) to afford4-[[4-(chloromethyl)phenyl]methyl]-7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octane6 (480 mg, 1.36 mmol, 52.55% yield) as brown sticky solid which wasstored in a round bottomed flask at 5° C. inside a refrigerator. LC MS:ES+ 345.32.

Step 4: Synthesis of6-[[4-[[7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one:To a well degassed solution of4-[[4-(chloromethyl)phenyl]methyl]morpholine 6 (8 g, 35.44 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one7 (20.92 g, 70.89 mmol) in Ethanol (4 mL)-Toluene (8 mL), Potassiumphosphate tribasic, anhydrous, (886.38 mg, 4.18 mmol) was added followedby the addition of Tri-o-Tolyl phosphine (84.73 mg, 278.38 umol) andPd₂(dba)₃ (127.46 mg, 139.19 umol). The resulting mixture was thenheated at 90° C. for 12 hours. After completion of reaction (asmonitored by LCMS), the reaction mixture was filtered through a bed ofcelite, washed with Ethyl acetate (200 mL). The combined filtrate wasthen washed with water (3×70 mL) and brine (2×50 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Crudemass was purified by flash chromatography, (gradient: 0-50% Ethylacetate in Hexane) to afford6-[[4-[[7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one8 (272 mg, 552.46 umol, 39.69% yield) as yellow solid which was storedin a Tarson plastic bottle at ambient temperature. LC MS: ES+ 478.2.

Step 5: Synthesis of3-[6-[[4-[[7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a ice cooled solution of6-[[4-[[7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one8 (150 mg, 314.09 umol) in dry THF (5 mL), Sodium hydride (60%dispersion in mineral oil) (120.35 mg, 3.01 mmol) was added portionwise, maintaining the temp <5° C. Once the addition is over, theresultant mixture was stirred for 15 minutes at room temperature. Thenthe reaction mixture was again cooled to 0° C. and3-bromopiperidine-2,6-dione 9 (301.54 mg, 1.57 mmol) was added to itportion wise. After complete addition, resulting solution was heated at70° C. for 1 hour. After completion (evidenced from TLC), the reactionmixture was again cooled to 0° C. and quenched with ice cooled water (15mL). Aqueous part was extracted with ethyl acetate (2×20 mL). Combinedextracts was dried over anhydrous sodium sulfate and concentrated underreduced pressure. Crude mass was purified by Preparative TLC Plate (2.5%MeOH in DCM as eluent) to afford3-[6-[[4-[[7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 135 (62 mg, 105.08 umol, 33.46% yield) as yellow solid whichwas stored in a round bottomed flask at 5° C. inside a refrigerator. 1HNMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.31 (d, J=8.24 Hz, 1H), 8.07(d, J=6.96 Hz, 1H), 7.80 (t, J=7.56 Hz, 1H), 7.38 (d, J=7.28 Hz, 1H),7.23-7.17 (m, 4H), 7.10-7.01 (m, 4H), 6.95-6.93 (m, 1H), 5.44 (dd,J=12.68, 4.96 Hz, 1H), 4.36 (m, 2H), 3.75 (s, 2H), 2.99-2.98 (m, 2H),2.94-2.87 (m, 3H), 2.79-2.62 (m, 4H), 2.10-2.07 (m, 1H), 0.65 (br s,2H), 0.54 (br s, 2H); LC MS: ES+ 589.6.

Example 52. Synthesis of3-[2-oxo-6-(prop-2-ynylamino)benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 136)

Step 1: Synthesis of 6-(benzhydrylideneamino)-1H-benzo[cd]indol-2-one:To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (1 g, 4.03mmol) and diphenylmethanimine (1.10 g, 6.05 mmol) in dioxane (15 mL),sodium tert-butoxide (1.16 g, 12.09 mmol) was added. Resulting mixturewas degassed with argon and tBuXPhos (342.35 mg, 806.21 umol) andPd2(dba)3 (738.27 mg, 806.21 umol) were added under inert atmosphere.Resulting mixture was heated at 100° C. for 16 h. After completion,reaction mixture was diluted with ethyl acetate, filtered through ashort pad of celite and washed with ethyl acetate. Combined organic partwas washed with water, brine, dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure. Crude mass waspurified by column chromatography (30% ethyl acetate-hexane) to afford6-(benzhydrylideneamino)-1H-benzo[cd]indol-2-one (350 mg, 1.00 mmol, 25%yield) as yellow solid. LCMS: m/z 349 [M+H]⁺.

Step 2: Synthesis of3-(6-((diphenylmethylene)amino)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:3-(6-((diphenylmethylene)amino)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione wassynthesized following same procedure as described in scheme-4, step-4above in 36% yield. LCMS: m/z 460 [M+H]⁺.

Step-3: Synthesis of3-(6-amino-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione hydrochloridesalt: Dioxane-HCl (4M, 2 mL, 8 mmol) was added3-[6-(benzhydrylideneamino)-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(200 mg, 435.26 umol) at 0° C. Resulting mixture was warmed to ambienttemperature and stirred for 16 h. After completion, reaction mixture wasconcentrated under reduced pressure, triturated with ether andlyophilized to afford3-(6-amino-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione (110 mg,331.57 umol, 76% yield, HCl salt) LCMS: m/z 296 [M+H]⁺.

Step 4: Synthesis of3-[2-oxo-6-(prop-2-ynylamino)benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of3-(6-amino-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione (100 mg,338.65 umol) in MeCN (10 mL) was added DIPEA (235.94 uL 1.35 mmol) at 0°C. and allowed to stir at RT for 30 min. 3-bromoprop-1-yne (60.43 mg,507.97 umol, 4.81 uL) was added at RT and resulting mixture was stirredat RT for 3 h. After completion, reaction mixture was concentrated underreduced pressure, diluted with ethyl acetate and separated. Organicportion was washed with water, brine, dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure. Crude masswas purified by combiflash chromatography (15-20%ethylacetate-dichloromethane) to afford3-[2-oxo-6-(prop-2-ynylamino)benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 136 (25 mg, 70.15 umol, 21% yield) LC MS: m/z 334 [M+H]⁺. 1HNMR (400 MHz, DMSO-d6) δ 11.07 (bs, 1H), 8.42 (d, J=8.2 Hz, 1H), 8.05(d, J=7.0 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 6.98 (d, J=7.7 Hz, 1H), 6.84(t, J=5.9 Hz, 1H), 6.45 (d, J=7.8 Hz, 1H), 5.40-5.36 (m, 1H), 4.06-4.04(m, 2H), 3.09 (s, 1H), 2.97-2.90 (m, 1H), 2.76-2.61 (m, 2H), 2.07-2.05(m, 1H).

Example 53. Synthesis of3-(2-oxo-6-prop-2-ynoxy-benzo[cd]indol-1-yl)piperidine-2,6-dione(Compound 137)

Step 1: Synthesis of6-hydroxy-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one: To a stirredsolution of1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indole-6-carbaldehyde (1 g,3.15 mmol) in DCM (15 mL) was added mCPBA (60% pure, 906.32 mg, 3.15mmol). Resulting mixture was stirred at 40° C. for 16 h. Aftercompletion, reaction mixture was cooled to 0° C. and methanolic ammonia(2M) was added drop wise till red wine color persisted. The reactionmixture was again stirred at 0° C. for 3 h. Reaction mixture wasneutralized with NaHCO₃ and extracted with DCM. Combined organic partwas washed with water, brine, dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure. Crude mass wastriturated with n-pentane to afford6-hydroxy-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (900 mg, 2.63mmol, 83% yield). LCMS: m/z 306 [M+H]⁺.

Step 2: Synthesis of 1-[(4-methoxyphenyl)methyl]-6-prop-2-ynoxy-benzo[cd]indol-2-one: To a stirred solution of6-hydroxy-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (700 mg, 2.29mmol) in acetone (10 mL) was added potassium carbonate (950.56 mg, 6.88mmol) at RT and allowed to stir for 30 min. Propargyl bromide (246.07uL, 2.75 mmol) was added and resulting reaction mixture was stirred atRT for 6 h. After completion, reaction mixture was poured into water,neutralized with 0.1 M HCl and extracted with ethyl acetate. Combinedorganic layer was washed with water, brine, dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure. Crude masswas triturated with n-pentane to afford 1-[(4-methoxyphenyl)methyl]-6-prop-2-ynoxy-benzo[cd]indol-2-one (300 mg, 873.68 umol, 38%yield) LCMS: m/z 344 [M+H]⁺.

Step 3: Synthesis of 6-prop-2-ynoxy-1H-benzo[cd]indol-2-one: To astirred solution of1-[(4-methoxyphenyl)methyl]-6-prop-2-ynoxy-benzo[cd]indol-2-one (250 mg,728.07 umol) in TFA (1.25 mL, 16.22 mmol) was added anisole (158.41 uL,1.46 mmol). Resulting solution was heated at 60° C. for 24 h. Reactionmixture was cooled to RT and TFA (1.25 mL, 16.22 mmol) and anisole(158.41 uL, 1.46 mmol) were again added and continued heating at 60° C.for additional 24 h. After completion, reaction mixture was cooled toRT, concentrated under reduced pressure, diluted with DCM andneutralized with Et₃N. It was washed with water, brine, dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure. Crude mass was purified by combiflash column chromatography(30% ethyl acetate-hexane) to afford6-prop-2-ynoxy-1H-benzo[cd]indol-2-one (90 mg, 385.08 umol, 55% yield)as a gum. LCMS: m/z 224 [M+H]⁺.

Step 4: Synthesis of3-(2-oxo-6-prop-2-ynoxy-benzo[cd]indol-1-yl)piperidine-2,6-dione: To astirred solution of 6-prop-2-ynoxy-1H-benzo[cd]indol-2-one (100 mg,447.98 umol) in THF (3 mL) was added sodium hydride (60% in mineral oil,102.99 mg, 4.48 mmol) slowly portion wise at 0° C. Resulting mixture wasstirred at RT for 30 min. 3-bromopiperidine-2,6-dione (430.08 mg, 2.24mmol) was added in portions at RT. Resulting mixture was heated at 60°C. for 5 h. After completion, reaction mixture was quenched with crushedice and extracted with ethyl acetate. Combined organic part was washedwith water, brine, dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure. Crude mass was purified by columnchromatography (70-80% ethylacetate-hexane) to afford3-(2-oxo-6-prop-2-ynoxy-benzo[cd]indol-1-yl)piperidine-2,6-dioneCompound 137 (11 mg, 32.61 umol, 8% yield). LCMS: m/z 335 [M+H]⁺. 1H NMR(400 MHz, DMSO-d6) δ 11.10 (bs, 1H), 8.27 (d, J=8.1 Hz, 1H), 8.13 (d,J=7.0 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 6.99 (d,J=7.8 Hz, 1H), 5.45-5.40 (m, 1H), 5.01 (s, 2H), 3.63 (s, 1H), 2.98-2.90(m, 1H), 2.78-2.62 (m, 2H), 2.10-2.07 (m, 1H).

Example 54. Synthesis of3-(6-bromo-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione, (Compound138)

Step 1: Synthesis of3-(6-bromo-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione: To a stirredsolution of 6-bromo-1H-benzo[cd]indol-2-one (4 g, 16.12 mmol) in THF(250 mL) and DMF (25 mL) was added Sodium hydride (60% dispersion inmineral oil) (6.18 g, 161.24 mmol, 60% purity) slowly portion wise at 0°C. Resultant mixture was stirred the reaction for 30 min at RT.3-bromopiperidine-2,6-dione (15.48 g, 80.62 mmol) was then added to itportion wise at RT and reaction mixture was heated to 70° C. andcontinued for 3 h. After completion, reaction was quenched with crushedice extracted with ethyl acetate. Combined organic part was washed withwater and brine. Organic layer was dried with anhydrous sodium sulphate,filtered and concentrated under reduced pressure. Crude mass waspurified by column chromatography (70% EA-hexane) to afford3-(6-bromo-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione Compound 138(2.6 g, 6.28 mmol, 40% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d6)δ 11.14 (s, 1H), 8.20 (d, J=7.0 Hz, 2H), 7.98 (t, J=7.7 Hz, 1H), 7.83(d, J=7.5 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 2.97-2.90 (m, 2H), 2.79-2.57(m, 2H), 2.12-2.10 (m, 1H).

Example 55. Synthesis of3-(2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (Compound 139)

Step 1: Synthesis of3-(2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To the stirredsolution of 1H-benzo[cd]indol-2-one 1 (100.0 mg, 591.09 umol) in DMF (2mL) was added Sodium hydride (in oil dispersion) 60% dispersion inmineral oil (24.91 mg, 650.20 umol, 60% purity) at 0° C. and then thereaction mixture was heated at 60° C. for 30 minutes followed by theaddition of 3-bromopiperidine-2,6-dione 2 (113.50 mg, 591.09 umol) andthe reaction mixture was heated at 60° C. for 24 hours. New spot formedalong with unreacted SM. 3-bromopiperidine-2,6-dione 2 (113.50 mg,591.09 umol) was topped up and the reaction mixture was again heated for24 hours. Reaction mixture was diluted with ethyl acetate, washed withwater and the organic fraction was separated. It was then dried overanhydrous sodium sulphate and evaporated under reduced pressure toobtain the crude compound which was purified by preparative TLC plate(eluting with 2% MeOH-DCM) to afford3-(2-oxobenzo[cd]indol-1-yl)piperidine-2,6-dione Compound 139 (10 mg,34.35 umol, 5.81% yield, 96.28% purity) as pale yellow solid. ¹H NMR(d6-DMSO, 400 MHZ) δ 11.13 (s, 1H), 8.24 (d, J=8.08 Hz, 1H), 8.11 (d,J=6.92 Hz, 1H), 7.84 (t, J=7.56 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.54(t, J=7.76 Hz, 1H), 7.17 (d, J=7.12 Hz, 1H), 5.46 (dd, J=12.76, 5.08 Hz,1H), 3.00-2.91 (m, 1H), 2.82-2.71 (m, 1H), 2.67-2.63 (m, 1H), 2.12-2.09(m, 1H); LC MS: ES+ 281.2.

Example 56. Synthesis of tert-butyl4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 140)

Step 1: Synthesis of 6-bromobenzo[cd]indol-2(1H)-one: To the stirredsuspension of 1H-benzo[cd]indol-2-one 1 (3.0 g, 17.73 mmol) in CHCl₃(50.0 mL) was added Bromine (2.15 g, 26.60 mmol, 1.44 mL) at coldcondition drop wise and the reaction mixture was continued at roomtemperature for 48 hours. Sodium thiosulphate solution was poured intothe reaction mixture in cold condition and the yellow solid formed wasfiltered through cintered funnel. Solid obtained was washed with coldwater, pentane and azeotroped with toluene to afford6-bromo-1H-benzo[cd]indol-2-one 2 (4 g, 16.12 mmol, 90.93% yield) asyellow solid. LC MS: ES+ 248.1, 250.0 (Bromo pattern).

Step 2: Synthesis of tert-butyl4-(4-(hydroxy(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:To the stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 2 (1.6 g,6.45 mmol) in THF (7 mL) was added Butyllithium (2.2 M, 9.38 mL) at −78°C. and after the addition was complete the temperature was allowed toincrease to −40° C. and the reaction mixture was stirred at the sametemperature for 30 minutes followed by the addition of tert-butyl4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate 3 (1.80 g, 6.45 mmol)in THF (7 mL) at −78° C. and then the reaction mixture was allowed towarm to room temperature and was continued for 16 hours. Reactionmixture was quenched with saturated aqueous ammonium chloride solution,diluted with ethyl acetate. Layers were separated and organic part waswashed with water. It was then dried over anhydrous sodium sulphate andevaporated under reduced pressure to obtain the crude compound which waspurified by flash chromatography using 0-5% MeOH-DCM to affordtert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate4 (527 mg, 1.17 mmol, 18.22% yield) as brown solid. 1H NMR (d6-DMSO, 400MHZ) δ 10.70 (s, 1H), 8.34 (d, J=8.28 Hz, 1H), 7.95 (d, J=6.96 Hz, 1H),7.72 (t, J=7.6 Hz, 1H), 7.59-7.52 (m, 2H), 7.28 (s, 1H), 6.93 (d, J=7.2Hz, 1H), 6.22 (br s, 1H), 5.80 (br s, 1H), 4.27-4.21 (m, 1H), 4.00-3.96(m, 2H), 2.84-2.82 (m, 2H), 1.91-1.87 (m, 2H), 1.72-1.64 (m, 2H), 1.39(s, 9H).

Step 3: Synthesis of 2,2,2-trifluoroacetaldehyde compound with6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one(1:1): To the stirred solution of tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate4 (500.0 mg, 1.11 mmol) in DCE (3 mL) was added Triethylsilane (518.51mg, 4.46 mmol, 712.24 uL) and Trifluoroacetic acid (1.02 g, 8.92 mmol,687.08 uL) and the reaction was continued for 30 minutes under microwavecondition at 70° C. The solvent in the reaction mixture was evaporatedunder reduced pressure to obtain the crude which was washed with etherand pentane to afford6-[(1-piperidin-1-ium-4-ylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one;2,2,2-trifluoroacetate5 (500.0 mg, 1.12 mmol, 100.47% yield) as brown gum in the form ofcrude. LC MS: ES+ 333.0.

Step 4: Synthesis of tert-butyl4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:To the stirred solution of6-[(1-piperidin-1-ium-4-ylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one;2,2,2-trifluoroacetate5 (500.0 mg, 1.12 mmol) in DCM (5 mL) was added Triethylamine (340.00mg, 3.36 mmol, 468.32 uL) at cold condition followed by the addition ofDi-tert-butyl dicarbonate (366.67 mg, 1.68 mmol, 385.56 uL) and thereaction was continued at room temperature for 16 hours. Reactionmixture was diluted with ethyl acetate, washed with water, brinesolution and the organic fraction was separated. It was then dried overanhydrous sodium sulphate and evaporated under reduced pressure toobtain the crude which was purified by flash chromatography (using 0-5%MeOH-DCM) to afford tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate6 (300.0 mg, 693.62 umol, 61.93% yield) as yellow sticky solid. LC MS:ES+ 433.0.

Step 5: Synthesis of tert-butyl4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:To the stirred solution of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate6 (300.0 mg, 693.62 umol) in DMF (1 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (53.15 mg, 1.39 mmol, 60%purity) in cold condition and the reaction mixture was heated at 60° C.for 30 minutes. Then to it was added 3-bromopiperidine-2,6-dione 7(133.18 mg, 693.62 umol) and the reaction was heated at 60° C. for 4hours followed by the further addition of 3-bromopiperidine-2,6-dione(133.18 mg, 693.62 umol) and the reaction was further continued for 16hours at 60° C. Reaction mixture was diluted with ethyl acetate, washedwith water and the organic fraction was separated. It was then driedover anhydrous sodium sulphate and evaporated under reduced pressure toobtain the crude which was first purified by column chromatographyfollowed by the preparative TLC plate purification (eluting with 60%ethyl acetate-hexane) to afford tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylateCompound 140 (20.0 mg, 33.11 umol, 4.77% yield, 90% purity) as paleyellow solid. ¹H NMR (d6-DMSO, 400 MHZ) δ 11.11 (s, 1H), 8.37 (d, J=8.24Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.83 (t, J=7.58 Hz, 1H), 7.59 (s, 1H),7.35 (d, J=7.36 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43(dd, J=12.76, 5.0 Hz, 1H), 4.24-4.23 (m, 1H), 4.17 (s, 2H), 4.00-3.96(m, 2H), 2.96-2.66 (m, 5H), 2.09-2.06 (m, 1H), 1.91-1.88 (m, 2H),1.72-1.66 (m, 2H), 1.39 (m, 9H); LC MS: ES+ 544.3.

Example 57. Synthesis of tert-butyl4-[4-[[1-[2,6-dioxo-3-piperidyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate(Compound 141) and tert-butyl4-[4-[[1-[2,6-dioxo-3-piperidyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate(Compound 142)

Step 1: Chiral separation: 150 mg of the racemate Compound 140 wassubmitted to Chiral Prep HPLC purification. The isomers were separatedand isolated by reverse phase chiral HPLC to afford tert-butyl4-[4-[[1-[2,6-dioxo-3-piperidyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylateCompound 141 (27.0 mg, 49.22 umol, 2.66% yield, 99.1% purity) andtert-butyl4-[4-[[1-[2,6-dioxo-3-piperidyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylateCompound 142 (26.0 mg, 47.83 umol, 2.59% yield, 100% purity) both asyellow solid.

Example 58. Synthesis of tert-butyl4-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 143)

Step 1: Synthesis of tert-butyl4-(4-(2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:To the stirred solution of tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate1 (500 mg, 1.11 mmol) in DCM (15.0 mL) was added dioxomanganese (969.17mg, 11.15 mmol) at 0° C. and the reaction mixture was stirred at roomtemperature for 16 hours. Reaction mixture was then filtered throughcelite bed and filtrate was then concentrated under reduced pressure toafford the crude material. The crude was then purified by columnchromatography by (eluting 1.5%-2% MeOH in DCM) to afford tert-butyl4-[4-(2-oxo-1H-benzo[cd]indole-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylate2 (220 mg, 492.72 umol, 44.20% yield) as green solid. LC MS: ES+ 447.4.

Step 2: Synthesis of tert-butyl4-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:In a round bottomed flask under nitrogen atmosphere tert-butyl4-[4-(2-oxo-1H-benzo[cd]indole-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylate2 (220 mg, 492.72 umol) was taken in DMF (3.0 mL) and then at 0° C.Sodium hydride (in oil dispersion) 60% dispersion in mineral oil (22.66mg, 985.45 umol) was added portion wise into the reaction mixture. Itwas then heated at 60° C. for 30 minutes and then3-bromopiperidine-2,6-dione (94.61 mg, 492.72 umol) was added into thereaction mixture. It was stirred for 16 hours at room temperature. Again3-bromopiperidine-2,6-dione (94.61 mg, 492.72 umol) was added and thenit was heated at 60° C. for 16 hours. Reaction mixture was cooled toroom temperature and extracted with ethyl acetate. Organic layer wasseparated, dried over sodium sulfate and concentrated under reducedpressure to afford the crude compound. Crude material was the purifiedby Preparative TLC Plate (eluting with 50% ethyl acetate indichloromethane) to afford tert-butyl4-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indole-6-carbonyl]pyrazol-1-yl]piperidine-1-carboxylateCompound 143 (15 mg, 26.90 umol, 5.46% yield) as a white solid. ¹H NMR(D6-DMSO, 400 MHZ) δ 11.17 (s, 1H), 8.58 (d, J=8.32 Hz, 1H), 8.46 (s,1H), 8.18 (d, J=6.96 Hz, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.99 (s, 1H), 7.92(t, J=7.7 Hz, 1H), 7.25 (d, J=7.56 Hz, 1H), 5.53 (dd, J=12.8, 5.28 Hz,1H), 4.49-4.44 (m, 1H), 4.07-4.03 (m, 2H), 3.01-2.66 (m, 5H), 2.18-2.14(m, 1H), 2.06-2.02 (m, 2H), 1.88-1.80 (m, 2H), 1.41 (s, 9H); LC MS: ES+558.5.

Example 59. Synthesis of3-(6-Amino-2-oxo-2H-benzo[cd]indol-1-yl)-piperidine-2,6-dionehydrochloride (Compound 144)

Step 1: Synthesis of 6-(Benzhydrylidene-amino)-1H-benzo[cd]indol-2-one:To a well degassed stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 1(1.0 g, 4.03 mmol) and diphenylmethanimine 2 (1.10 g, 6.05 mmol, 1.01mL) in dry grade Toluene (5.0 mL), sodium;2-methylpropan-2-olate (1.16g, 12.09 mmol),(5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane(466.49 mg, 806.21 umol) and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one;palladium (369.13 mg, 403.10 umol) were added. After complete addition,reaction mixture was heated at 80° C. in a sealed tube for 12 hours.Reaction mass was filtered through celite and the filtrate wasconcentrated under reduced pressure. The crude thus obtained waspurified by combi-flash to get the pure compound6-(benzhydrylideneamino)-1H-benzo[cd]indol-2-one 3 (565 mg, 1.62 mmol,40.23% yield) as light brown solid. LC MS: ES+ 349.2.

Step 2: Synthesis of3-[6-(Benzhydrylidene-amino)-2-oxo-2H-benzo[cd]indol-1-yl]-piperidine-2,6-dione:To the stirred solution of6-(benzhydrylideneamino)-1H-benzo[cd]indol-2-one 3 (293 mg, 841.00 umol)in dry DMF (3.0 mL), Sodium hydride (in oil dispersion) 60% dispersionin mineral oil (100.92 mg, 4.20 mmol) was added at 0° C. and resultantsolution was heated at 70° C. for 1 hour. After that,3-bromopiperidine-2,6-dione 4 (322.96 mg, 1.68 mmol) was added to thereaction mixture and heating was continued for 12 hours. Reaction wasmonitored by TLC which showed incomplete consumption of the6-(benzhydrylideneamino)-1H-benzo[cd]indol-2-one 3 along with desiredspot as confirmed from LCMS. For complete completion of reaction further3-bromopiperidine-2,6-dione (322.96 mg, 1.68 mmol) was added to thereaction mixture and heating was continued for further 6 hours. Afteralmost completion of reaction (˜65% as confirmed by LC MS), reactionmixture was quenched with saturated ammonium chloride solution andextracted with ethyl acetate. Organic phase was separated, dried oversodium sulfate and concentrated under vacuum. Crude residual part waspurified combi-flash (30% DCM in ethyl acetate) to afford3-[6-(benzhydrylideneamino)-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione5 (70 mg, 152.34 umol, 18.11% yield) as light yellow solid. LC MS: ES+460.3.

Step 3: Synthesis of3-(6-Amino-2-oxo-2H-benzo[cd]indol-1-yl)-piperidine-2,6-dionehydrochloride: 4.0 M dioxane-HCl(2.0 mL) was added to the3-[6-(benzhydrylideneamino)-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione5 (60 mg, 130.58 umol) followed by 0.2 ml of water at 0° C. and stirredfor 3 hours at room temperature. Volatiles were removed under reducedpressure.

Crude solid material was washed with DCM and ether several times. Solidmaterial was lyophilized to afford HCl salt of3-(6-amino-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione Compound 144(45.0 mg, 122.08 umol, 93.49% yield, 90% purity, 021) as brown solid. ¹HNMR (d6 DMSO, 400 MHz) δ 11.06 (s, 1H); 8.40 (d, J=8.04 Hz, 1H),8.05-8.03 (m, 1H), 7.72 (m, 1H), 6.91-6.89 (m, 1H), 6.62-6.59 (m, 1H),5.37-5.35 (m, 1H), 2.92-2.88 (m, 1H), 2.71-2.59 (m, 2H), 2.06-2.04 (m,1H); LC MS: ES+ 296.3.

Example 60. Synthesis of1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonitrile(Compound 145)

Step 1: Synthesis of 2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonitrile: Toa stirred solution of 6-bromo-1H-benzo[cd]indol-2-one 1 (5 g, 20.16mmol) in NMP (25 mL) was added cuprous; cyanide (3.61 g, 40.31 mmol,1.24 mL) and the reaction was stirred at 120° C. for 16 h. LCMS showed15% product formation along with unreacted SM. Again cuprous; cyanide(3.61 g, 40.31 mmol, 1.24 mL) was added and the reaction was continuedfor 48 h. LCMS showed formation of desired compound. The reactionmixture was diluted with ethyl acetate and washed with water and brine,dried over sodium sulphate and concentrated. The crude was purified bycolumn chromatography in 100-200 silica to afford2-oxo-1H-benzo[cd]indole-6-carbonitrile 2 (1.5 g, 6.18 mmol, 30.66%yield, 80% purity) as yellow solid. LC MS: ES+ 195.4.

Step 2: Synthesis of1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonitrile:To the stirred solution of 2-oxo-1H-benzo[cd]indole-6-carbonitrile 2(250 mg, 1.29 mmol) in DMF (4.0 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (98.66 mg, 2.57 mmol, 60%purity) and then it was heated at 70° C. for 1 hour. After that to it3-bromopiperidine-2,6-dione 3 (247.20 mg, 1.29 mmol) was added underroom temperature and then it was stirred at 70° C. for 16 hours. TLC waschecked which shows that the starting material was present a polar newspot was formed. Again, into the reaction mixture3-bromopiperidine-2,6-dione 3 (247.20 mg, 1.29 mmol) was added and thenit was stirred at 70° C. for 16 hours. The reaction mixture was thencooled to room temperature and it was then extracted with ethyl acetate.The organic part was then dried over sodium sulfate to afford the crudematerial. The crude was then purified by Preparative TLC method byeluting (40% ethyl acetate in dichloromethane) to afford1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indole-6-carbonitrile Compound145 (8 mg, 26.01 umol, 2.02% yield, 99.26% purity) as a white solid. ¹HNMR (d6 DMSO, 400 MHz) δ 11.19 (s, 1H), 8.31-8.22 (m, 3H), 8.07-8.06 (m,1H), 7.36 (d, J=7.28 Hz, 1H), 5.53-5.51 (m, 1H), 2.95-2.90 (m, 1H),2.77-2.62 (m, 2H), 2.14-2.12 (m, 1H); LC MS: ES− 304.1.

Example 61. Synthesis of3-[6-[[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 146)

Step 1: Synthesis of6-[[4-(chloromethyl)phenyl]methyl]-3-oxa-6-azabicyclo[3.1.1]heptane: Toa stirred solution of 3-oxa-6-azabicyclo[3.1.1]heptane; hydrochloride(2) (800 mg, 5.90 mmol, 1.00 mL) in Acetone (15 mL), Potassiumcarbonate, anhydrous, 99% (1.22 g, 8.85 mmol, 534.14 uL) was added andthe resultant reaction mixture was stirred at 50° C. for 20 minutesfollowed by the addition of 1,4-bis(chloromethyl)benzene (1) (1.03 g,5.90 mmol, 727.35 uL). Resulting solution was further heated at sametemperature for 3 hours. After completion (monitored by TLC and LCMS),all the volatiles were removed under reduced pressure and re-dissolvedin ethyl acetate. Organic portion was washed with water and brine, driedover sodium sulfate and concentrated. The crude thus obtained waspurified by column chromatography in (gradient: 0-30% EtOAc in DCM) toafford6-[[4-(chloromethyl)phenyl]methyl]-3-oxa-6-azabicyclo[3.1.1]heptane 3(800 mg, 51.33% yield) as yellow gum. LC MS: ES+ 238.2.

Step 2: Synthesis of6-[[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of6-[[4-(chloromethyl)phenyl]methyl]-3-oxa-6-azabicyclo[3.1.1]heptane (3)(600 mg, 2.52 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(4) (1.49 g, 5.05 mmol) in ethanol (5 mL) and Toluene (10 mL) was addedPotassium phosphate tribasic anhydrous (1.61 g, 7.57 mmol) and thereaction mass was degassed under nitrogen atmosphere over 10 minutes.Then Tri-o-Tolyl phosphine (153.64 mg, 504.79 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (231.12 mg, 252.39umol) was added to this reaction mass and at 90° C. for 18 hours. Aftercompletion (monitored by TLC) the reaction mixture was passed throughcelite bed and washed with EtOAc. The filtrate was further washed withwater and brine, dried over sodium sulphate and concentrated. The crudethus obtained was purified by combiflash chromatography in (gradient:0-30% EtOAc in DCM) to afford the desired compound6-[[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one(5) (300 mg, 24.39% yield). LC MS: ES+ 371.3.

Step 3: Synthesis of3-[6-[[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one(5) (150 mg, 404.92 umol) in dry THF (10 mL) Sodium hydride 60%dispersion in mineral oil (93.09 mg, 4.05 mmol) was added at 0° C. andstirred for 15 minutes followed by the addition of3-bromopiperidine-2,6-dione (6) (388.75 mg, 2.02 mmol). The resultingreaction mixture was stirred at 70° C. for 1 hr. After completion(monitored by TLC and LCMS), the reaction mixture was quenched in iceand extracted with ethyl acetate. Organic layer was further washed withwater and brine, dried over sodium sulfate and concentrated. The crudethus obtained was purified by PREP-TLC (10% MeOH in EtOAc as eluent) toafford3-[6-[[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 146 (90.0 mg, 41.54% yield) as yellow solid. ¹H NMR (DMSO-d₆,400 MHz) δ 11.11 (s, 1H), 8.32 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.96 Hz,1H), 7.80 (t, J=7.8 Hz, 1H), 7.40 (d, J=7.32 Hz, 1H), 7.26-7.20 (m, 4H),7.09 (d, J=7.24 Hz, 1H), 5.46-5.41 (m, 1H), 4.36 (s, 2H), 4.10 (d,J=10.68 Hz, 1H), 3.69 (s, 2H), 3.57 (d, J=10.68 Hz, 1H), 3.39-3.33 (m,2H), 2.97-2.90 (m, 1H), 2.79-2.73 (m, 1H), 2.70-2.63 (m, 1H), 2.10-2.07(m, 2H), 1.87-1.85 (m, 2H), 1.71-1.67 (m, 1H); LC MS: ES+ 482.2.

Example 62. Synthesis of tert-butyl4-(4-(1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)ethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 147)

Step 1: Synthesis of tert-butyl4-(4-(1-hydroxy-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)ethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:To the stirred solution of tert-butyl4-[4-(2-oxo-1H-benzo[cd]indole-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylate1 (400.0 mg, 895.86 umol) in THF (10 mL) was added Methylmagnesiumbromide, 3M in ether (3 M, 1.49 mL) at −50° C. After completion ofaddition the reaction mixture was allowed to warm to room temperatureand continued at room temperature for 16 hours. The reaction mixture wasquenched with ammonium chloride solution, diluted with ethyl acetate,washed with water and the organic fraction was separated. It was driedover anhydrous sodium sulphate and evaporated under reduced pressure toobtain the crude compound which was purified by flash chromatographyusing 0-5% MeOH-DCM to afford tert-butyl4-[4-[1-hydroxy-1-(2-oxo-1H-benzo[cd]indol-6-yl)ethyl]pyrazol-1-yl]piperidine-1-carboxylate2 (285.0 mg, 611.23 umol, 68.23% yield, 99.2% purity) as brown solid. LCMS: ES− 461.2.

Step 2: Synthesis of 2,2,2-trifluoroacetaldehyde compound with6-(1-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)ethyl)benzo[cd]indol-2(1H)-one(1:1): To the stirred solution of tert-butyl4-[4-[1-hydroxy-1-(2-oxo-1H-benzo[cd]indol-6-yl)ethyl]pyrazol-1-yl]piperidine-1-carboxylate2 (284.0 mg, 614.00 umol) in DCE (2 mL) was added Triethylsilane (285.58mg, 2.46 mmol, 392.29 uL), Trifluoroacetic acid (560.07 mg, 4.91 mmol,378.42 uL) and the reaction was heated at 80° C. in a sealed tube for 2hours. The solvent in the reaction mixture was evaporated under reducedpressure to obtain the crude compound which was triturated with ether toafford[4-[4-[1-(2-oxo-1H-benzo[cd]indol-6-yl)ethyl]pyrazol-1-yl]-1-piperidyl]2,2,2-trifluoroacetate3 (280.0 mg, 462.55 umol, 75.33% yield, 94.9% purity) as brown gum whichwas used directly in the next step. LC MS: ES+ 347.2.

Step 3: Synthesis of tert-butyl4-(4-(1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)ethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:To the stirred solution of[4-[4-[1-(2-oxo-1H-benzo[cd]indol-6-yl)ethyl]pyrazol-1-yl]-1-piperidyl]2,2,2-trifluoroacetate3 (280.0 mg, 608.10 umol) in DCM (5 mL) was added Triethylamine (184.60mg, 1.82 mmol, 254.27 uL) at 0° C. followed by the addition ofDi-tert-butyl dicarbonate (199.08 mg, 912.16 umol, 209.33 uL) and thereaction was continued at room temperature for 16 hours. TLC was checkedwhich showed complete consumption of the starting material along withthe formation of the desired spot. The reaction mixture was diluted withethyl acetate, washed with water, the organic fraction was separated,dried over anhydrous sodium sulphate and evaporated under reducedpressure to obtain the crude compound which was purified by flashchromatography using 0-5% MeOH-DCM to afford tert-butyl4-[4-[1-(2-oxo-1H-benzo[cd]indol-6-yl)ethyl]pyrazol-1-yl]piperidine-1-carboxylate4 (190.0 mg, 414.01 umol, 68.08% yield, 97.3% purity) as brown solid. LCMS: ES+ 447.3 Step 4: Synthesis of tert-butyl4-(4-(1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)ethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:To the stirred solution of tert-butyl4-[4-[1-(2-oxo-1H-benzo[cd]indol-6-yl)ethyl]pyrazol-1-yl]piperidine-1-carboxylate4 (190.0 mg, 425.49 umol) in DMF (2 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (81.52 mg, 2.04 mmol, 60%purity) in cold condition and the reaction mixture was heated at 60° C.for 1 hour followed by the addition of 3-bromopiperidine-2,6-dione 5(163.40 mg, 850.99 umol) and the reaction was continued for 4 hours at60° C. with further top up of 3-bromopiperidine-2,6-dione 5 (163.40 mg,850.99 umol) and the reaction was continued for 16 hours at 60° C. Thereaction mixture was added to a solution of citric acid (pH 5) and theextracted with ethyl acetate. The organic fraction was separated, driedover anhydrous sodium sulphate and evaporated under reduced pressure toobtain the crude which was first purified by flash chromatography using(0-60% ethyl acetate DCM) followed by further purification bypreparative TLC plate method developing the plate in (45% ethylacetate-DCM) to afford tert-butyl4-[4-[1-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]ethyl]pyrazol-1-yl]piperidine-1-carboxylateCompound 147 (20.0 mg, 35.87 umol, 8.43% yield, 100% purity) as yellowsolid. ¹H NMR (400 MHz, DMSO-d6): 11.11 (s, 1H), 8.40 (d, J=8.2 Hz, 1H),8.08 (d, J=6.92 Hz, 1H), 7.81 (t, J=7.68 Hz, 1H), 7.62 (d, J=4.72 Hz,1H), 7.35-7.29 (m, 2H), 7.07 (d, J=7.44 Hz, 1H), 5.44-5.42 (m, 1H),4.78-4.76 (m, 1H), 4.25-4.24 (m, 1H), 3.98-3.97 (m, 2H), 2.95-2.72 (m,4H), 2.67-2.62 (m, 1H), 2.09-2.08 (m, 1H), 1.93-1.90 (m, 2H), 1.73-1.63(m, 5H), 1.39 (s, 9H); LC MS: ES− 556.2.

Example 63. Synthesis of Synthesis of3-(6-(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)ethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 148) and3-(6-(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)ethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 149)

Step 1: Synthesis of6-(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)ethyl)benzo[cd]indol-2(1H)-one:To the stirred solution of6-[1-[1-(4-piperidyl)pyrazol-4-yl]ethyl]-1H-benzo[cd]indol-2-one;2,2,2-trifluoroaceticacid 1 (589.26 mg, 1.28 mmol) in DMF (2 mL) was added HATU (729.90 mg,1.92 mmol) in cold condition followed by the addition1-methylcyclobutanecarboxylic acid 2 (160.68 mg, 1.41 mmol, 143.47 uL)and the reaction was continued at room temperature for 16 hours. Thereaction mixture was diluted with ethyl acetate, washed with sodiumbicarbonate solution, water and the organic fraction was separated. Itwas dried over anhydrous sodium sulphate and evaporated under reducedpressure to obtain the crude which was purified by flash chromatographyusing 0-5% MeOH-DCM to afford the desired compound as racemic mixture(350.0 mg) which was submitted for normal phase prep HPLC for theseparation of the chiral isomers to afford6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]ethyl]-1H-benzo[cd]indol-2-one3a (145.0 mg, 325.58 umol, 25.44% yield, 99.37% purity) and6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]ethyl]-1H-benzo[cd]indol-2-one3b (115.0 mg, 259.86 umol, 20.31% yield, 100% purity) both as yellowsolid. LC MS: ES+ 443.4.

Step 2a: Synthesis of3-(6-(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)ethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To the stirred solution of6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]ethyl]-1H-benzo[cd]indol-2-one3a (145.0 mg, 327.65 umol) in THF (6.0 mL) was added Sodium hydride (inoil dispersion) 60% dispersion in mineral oil (125.54 mg, 3.28 mmol, 60%purity) in cold condition and the reaction mixture was stirred at roomtemperature for 10 minutes followed by the addition of3-bromopiperidine-2,6-dione 4 (314.56 mg, 1.64 mmol) portion wise. Itwas then stirred at room temperature for 10 minutes and heated at 70° C.for 30 minutes. TLC was checked which showed formation of the desiredspot. The reaction mixture was diluted with ethyl acetate, washed withcold water and the organic fraction was separated. It was then driedover anhydrous sodium sulphate and evaporated under reduced pressure toobtain the crude which was purified by preparative TLC plate methodeluting the plate in 55% ethyl acetate-DCM to afford3-[6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]ethyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 148 (70.0 mg, 125.90 umol, 38.43% yield, 99.58% purity) asyellow solid. ¹H NMR (400 MHz, DMSO-d6): 11.11 (s, 1H), 8.40 (d, J=8.2Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.81 (t, J=7.54 Hz, 1H), 7.64-7.63 (m,1H), 7.35-7.29 (m, 2H), 7.07 (d, J=7.4 Hz, 1H), 5.44-5.42 (m, 1H),4.78-4.76 (m, 1H), 4.40-4.29 (m, 2H), 3.59-3.58 (m, 1H), 3.06-3.01 (m,1H), 2.98-2.91 (m, 1H), 2.78-2.62 (m, 3H), 2.41-2.32 (m, 3H), 2.08-2.07(m, 1H), 1.97-1.85 (m, 3H), 1.80-1.78 (m, 3H), 1.65-1.63 (m, 4H), 1.34(s, 3H); LC MS: ES+ 554.5.

Step 2b: Synthesis of3-(6-(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)ethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To the stirred solution of6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]ethyl]-1H-benzo[cd]indol-2-one3b (115.0 mg, 259.86 umol) in THF (5 mL) was added Sodium hydride (inoil dispersion) 60% dispersion in mineral oil (99.57 mg, 2.60 mmol, 60%purity) in cold condition and the reaction mixture was stirred at roomtemperature for 10 minutes followed by the addition of3-bromopiperidine-2,6-dione 4 (249.48 mg, 1.30 mmol) portion wise. Itwas then stirred at room temperature for 10 minutes and heated at 70° C.for 30 minutes. TLC was checked which showed formation of the desiredspot. The reaction mixture was diluted with ethyl acetate, washed withcold water and the organic fraction was separated. It was then driedover anhydrous sodium sulphate and evaporated under reduced pressure toobtain the crude which was purified by preparative TLC plate methodeluting the plate in 55% ethyl acetate-DCM to afford3-[6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]ethyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 149 (45.0 mg, 81.28 umol, 31.28% yield, 100% purity) as yellowsolid. ¹H NMR (400 MHz, DMSO-d6): 11.10 (s, 1H), 8.40 (d, J=8.16 Hz,1H), 8.08 (d, J=6.72 Hz, 1H), 7.81 (t, J=7.38 Hz, 1H), 7.64-7.63 (m,1H), 7.35-7.29 (m, 2H), 7.07 (d, J=7.2 Hz, 1H), 5.44-5.42 (m, 1H),4.78-4.76 (m, 1H), 4.40-4.29 (m, 2H), 3.59-3.58 (m, 1H), 3.06-3.01 (m,1H), 2.98-2.91 (m, 1H), 2.78-2.62 (m, 3H), 2.41-2.32 (m, 3H), 2.08-2.07(m, 1H), 1.97-1.85 (m, 3H), 1.80-1.78 (m, 3H), 1.65-1.63 (m, 4H), 1.34(s, 3H); LC MS: ES+ 554.5.

Example 64. Synthesis of3-(6-(4-((1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 150)

Step 1: Synthesis of tert-butyl4-(4-(ethoxycarbonyl)benzylidene)piperidine-1-carboxylate: To thestirred solution of ethyl 4-bromobenzoate 2 (7 g, 30.56 mmol, 5.00 mL)in DMF (20 mL) was added tert-butyl 4-methylenepiperidine-1-carboxylate1 (18.09 g, 91.67 mmol). It was degassed with argon for 10 minutes.Triethylamine (15.46 g, 152.79 mmol, 21.30 mL) and cyclopentyl(diphenyl) phosphane; dichloromethane; dichloropalladium; iron (2.50 g,3.06 mmol) were added to the reaction mixture. It was heated at 100° C.for 16 hours. It was cooled to RT, filtered through celite and washedwith ethyl acetate. The organic part was washed with water, brine driedover sodium sulfate and concentrated under reduced pressure. It waspurified by combiflash eluting at 10% ethyl acetate in hexane to affordtert-butyl 4-[(4-ethoxycarbonylphenyl)methylene]piperidine-1-carboxylate3 (8.2 g, 22.84 mmol, 74.73% yield, 96.2% purity) as colourless gum. LCMS: ES+ 346.2.

Step 2: Synthesis of tert-butyl4-(4-(ethoxycarbonyl)benzyl)piperidine-1-carboxylate: tert-butyl4-[(4-ethoxycarbonylphenyl)methylene]piperidine-1-carboxylate 3 (8.1 g,23.45 mmol, 6.09 mL) was taken in Ethyl acetate (75 mL). It was degassedwith argon for 10 minutes. Palladium on carbon 10% (2.50 g, 2.34 mmol,0.1 purity) was added to the reaction mixture. It was stirred at RT for16 hours. It was filtered through celite, concentrated under reducedpressure to afford tert-butyl4-[(4-ethoxycarbonylphenyl)methyl]piperidine-1-carboxylate 4 (8 g, 22.22mmol, 94.78% yield, 96.52% purity) as colourless gum. LC MS: ES+ 348.4.

Step 3: Synthesis of tert-butyl4-(4-(hydroxymethyl)benzyl)piperidine-1-carboxylate: To a stirredsolution of tert-butyl4-[(4-ethoxycarbonylphenyl)methyl]piperidine-1-carboxylate 4 (7.9 g,22.74 mmol) in THF (100 mL) was added Diisobutylaluminum hydride, 1Msolution in hexane (64.67 g, 113.69 mmol, 92.26 mL, 0.25 purity) at −78°C. drop wise. It was stirred at −78° C. for 2 h. It was quenched withsodium potassium tartrate solution, extracted with ethyl acetate, washedwith brine, dried over sodium sulfate and concentrated under reducedpressure. It was purified by combiflash eluting at 15% ethyl acetate inhexane to afford tert-butyl4-[[4-(hydroxymethyl)phenyl]methyl]piperidine-1-carboxylate 5 (4.5 g,13.26 mmol, 58.32% yield, 90% purity) as colourless gum. LC MS: ES+306.2.

Step 4: Synthesis of tert-butyl4-(4-(chloromethyl)benzyl)piperidine-1-carboxylate: To a stirredsolution of tert-butyl4-[[4-(hydroxymethyl)phenyl]methyl]piperidine-1-carboxylate 5 (4.4 g,14.41 mmol) in DCM (40 mL) was added Triethylamine (8.75 g, 86.44 mmol,12.05 mL) drop wise at 0° C. Thionyl Chloride (5.14 g, 43.22 mmol) wasadded to the reaction mixture very slowly and stirred at RT for 16hours. It was diluted with ethyl acetate, washed with water, brine,dried over sodium sulfate and concentrated under reduced pressure. Itwas purified by combiflash eluting at 15% ethyl acetate in hexane toafford tert-butyl4-[[4-(chloromethyl)phenyl]methyl]piperidine-1-carboxylate 6 (3.9 g,11.44 mmol, 79.41% yield, 95% purity) as off white solid. ¹H NMR (400MHz, DMSO-d6): δ 7.33 (d, J=7.8 Hz, 2H), 7.17 (d, J=7.76 Hz, 2H), 4.72(s, 2H), 3.90-3.87 (m, 2H), 2.71-2.63 (m, 2H), 1.65-1.63 (m, 1H),1.53-1.50 (m, 2H), 1.37 (s, 9H), 1.04-0.92 (m, 2H).

Step 5: Synthesis of tert-butyl4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperidine-1-carboxylate:To the stirred solution of tert-butyl4-[[4-(chloromethyl)phenyl]methyl]piperidine-1-carboxylate 6 (780 mg,2.41 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one7 (1.07 g, 3.61 mmol) in a sealed tube in Ethanol (6 mL) and Toluene (12mL) were added tripotassium; phosphate (1.28 g, 6.02 mmol). It wasdegassed with argon for 10 minutes. tris-o-tolylphosphane (146.61 mg,481.69 umol) and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium(220.55 mg, 240.85 umol) were added to the reaction mixture. It washeated at 90° C. for 16 hours. It was cooled to RT, filtered throughcelite, concentrated under reduced pressure. It was purified bycombiflash eluting at 30% ethyl acetate in hexane to afford tert-butyl4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperidine-1-carboxylate8 (680 mg, 1.34 mmol, 55.65% yield, 90% purity) as yellow solid. LC MS:ES+ 457.3.

Step 6: Synthesis of tert-butyl4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperidine-1-carboxylate:To a stirred solution of tert-butyl4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperidine-1-carboxylate8 (680 mg, 1.49 mmol) in THF (10 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (570.67 mg, 14.89 mmol, 0.6purity) portion wise at 0° C. It was stirred at RT for 10 minutes.tert-butyl4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperidine-1-carboxylate9 (680 mg, 1.49 mmol) was added to the reaction mixture at RT portionwise. It was heated at 70° C. for 1 hour. It was cooled to RT, dilutedwith ethyl acetate, poured to ice cold water, separated organic part,washed with water, brine and dried over sodium sulfate. It wasevaporated under reduced pressure. It was purified by preparative TLC(20% ethyl acetate in DCM) to afford tert-butyl4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]piperidine-1-carboxylate10 (690 mg, 1.17 mmol, 78.82% yield, 96.58% purity) as yellow solid. LCMS: ES+ 568.6.

Step 7: Synthesis of3-(2-oxo-6-(4-(piperidin-4-ylmethyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dionehydrochloride: To a stirred solution of tert-butyl4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]piperidine-1-carboxylate10 (685 mg, 1.21 mmol) in Dioxane (5 mL) was added 4M Dioxane-HCl (1.21mmol, 10 mL) at 0° C. It was stirred at RT for 3 hours. It wasconcentrated under reduced pressure to afford3-[2-oxo-6-[[4-(4-piperidylmethyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione, hydrochloride 11(650 mg, 1.01 mmol, 84.06% yield, 90.76% purity) as yellow solid. LC MS:ES+ 468.1.

Step 8: Synthesis of3-(6-(4-((1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To a stirred solution of3-[6-[[4-[(1-chloro-4-piperidyl)methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione,hydrochloride 11 (100 mg, 198.41 umol) in DMF (5 mL) was added DIPEA(128.21 mg, 992.03 umol, 172.79 uL) at 0° C. It was stirred at RT for 10minutes. 1-methylcyclobutanecarboxylic acid 12 (22.65 mg, 198.41 umol)and followed by HATU (90.53 mg, 238.09 umol) were added to the reactionmixture. It was stirred at RT for 16 h. It was diluted with ethylacetate, washed with saturated bicarbonate solution, brine and driedover sodium sulfate. It was purified combiflash eluting at 20% ethylacetate in dichloromethane to afford3-[6-[[4-[[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 150 (40.0 mg, 68.61 umol, 34.58% yield, 96.68% purity) asyellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.2Hz 1H), 8.07 (d, J=6.92 Hz 1H), 7.80 (t, J=7.6 Hz, 1H), 7.39 (d, J=7.24Hz, 1H), 7.19 (d, J=7.84 Hz, 2H), 7.10-7.04 (m, 3H), 5.45-5.43 (m, 1H),4.35 (s, 2H), 4.35-4.21 (m, 1H), 3.5-3.4 (m, 1H), 2.94-2.30 (m, 1H),2.84-2.70 (m, 2H), 2.70-2.62 (m, 1H), 2.44-2.41 (m, 2H), 2.37-2.39 (m,2H), 2.10-2.07 (m 1H), 1.88-1.86 (m, 1H), 1.38-1.52 (m, 6H), 1.28 (s,3H), 0.98-0.92 (m, 3H); LC MS: ES+ 564.2.

Example 65. Synthesis of4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperidin-1-yl)-3-fluorobenz° nitrite (Compound 151)

Step 1: Synthesis of4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperidin-1-yl)-3-fluorobenzonitrile:To a stirred solution of3-[2-oxo-6-[[4-(4-piperidylmethyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione;hydrochloride 1 (150 mg, 297.61 umol) in 1-methylpyrrolidin-2-one (1.55g, 15.59 mmol, 1.5 mL), N-ethyl-N-isopropyl-propan-2-amine (230.78 mg,1.79 mmol, 311.03 uL) was added to it under inert atmosphere in a sealtube. 3,4-difluorobenzonitrile 2 (49.68 mg, 357.13 umol) was added tothe reaction mixture and the combined reaction mixture was placed on apreheated oil bath (70° C.) and reaction was continued at the sametemperature for 16 hours. The reaction progression was monitored throughTLC. After completion of the reaction ethyl acetate was added to thereaction mixture and the organic layer was washed with water andsaturated bicarbonate solution. The ethyl acetate layer was dried oversodium sulfate and concentrated under reduced pressure. the crudeproduct was purified through flash chromatography using 2% methanol DCMto afford4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]-1-piperidyl]-3-fluoro-benzonitrileCompound 151 (40.0 mg, 67.50 umol, 22.68% yield, 99% purity) as yellowsolid. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.33 (d, J=8.28 Hz,1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.64 Hz, 1H), 7.63 (d, J=6.74Hz, 1H), 7.51 (d, J=8.32 Hz, 1H), 7.40 (d, J=7.32 Hz, 1H), 7.20 (d,J=7.8 Hz, 2H), 7.11-7.04 (m, 4H), 5.44 (dd, J=12.76, 5.0 Hz, 1H), 4.36(s, 2H), 3.51-3.48 (m, 2H), 2.30-2.92 (m, 1H), 2.77-2.62 (m, 4H),2.50-2.41 (m, 2H), 2.10-2.07 (m, 1H), 1.62-1.59 (m, 3H), 1.27-1.25 (m,2H); LC MS: ES+ 587.2.

Example 66. Synthesis of3-(6-(4-((1-benzylpiperidin-4-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 152)

Step 1: Synthesis of3-(6-(4-((1-benzylpiperidin-4-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To a stirred solution of3-[2-oxo-6-[[4-(4-piperidylmethyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione;hydrochloride 1 (150 mg, 297.61 umol) in THF (7 mL),N-ethyl-N-isopropyl-propan-2-amine (38.46 mg, 297.61 umol, 51.84 uL) wasadded and the combined reaction mixture was stirred for 5 mins undernitrogen atmosphere at 0° C. in a sealed tube. After that benzaldehyde 2(31.58 mg, 297.61 umol, 30.37 uL), dibutyltin(2+);dichloride (108.51 mg,357.13 umol, 79.79 uL), phenylsilane (32.21 mg, 297.61 umol, 36.68 uL)were added to the reaction mixture. The combined reaction mixture wasplaced in a preheated oil bath (90° C.). The reaction was continued atthe same temperature for 16 hours. The reaction progression wasmonitored through TLC. After completion of the reaction THF part wasconcentrated under reduced pressure and ethyl acetate was added to thecrude reaction mixture. The ethyl acetate layer was washed with waterand saturated sodium bicarbonate solution and the organic layer wasdried over sodium sulfate. The organic layer was concentrated underreduced pressure and the crude product was purified through flashchromatography using 1.5%-2% methanol DCM to afford3-[6-[[4-[(1-benzyl-4-piperidyl)methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 152 (90.0 mg, 154.09 umol, 51.78% yield, 95.48% purity) asyellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.31 (d, J=8.24Hz, 1H), 8.06 (d, J=6.92 Hz, 1H), 7.79 (t, J=7.62 Hz, 1H), 7.38 (d,J=7.32 Hz, 1H), 7.31-7.18 (m, 7H), 7.09 (d, J=7.28 Hz, 1H), 7.03 (d,J=7.80 Hz, 2H), 5.43 (dd, J=12.72, 5.0 Hz, 1H), 4.34 (s, 2H), 3.38 (s,2H), 2.94-2.91 (m, 1H), 280-2.62 (m, 4H), 2.42-2.40 (m, 2H), 2.09-2.07(m, 1H), 1.82-1.77 (m, 2H), 1.48-1.41 (m, 3H), 1.17-1.09 (m, 2H); LC MS:ES+ 558.35.

Example 67. Synthesis of3-(6-(amino(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 153)

Step 1: Synthesis of tert-butyl4-(4-(2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(2): To a stirred solution of tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate1 (2 g, 4.46 mmol) in DCM at room temperature dioxomanganese (3.88 g,44.59 mmol) was added at inert atmosphere. The combined reaction mixturewas stirred for 15 h. The reaction progression was monitored throughTLC. After completion of the reaction, the reaction mixture was passedthrough celite to remove dioxomanganese and the filtrate wasconcentrated under reduced pressure. The crude product was purifiedthrough column chromatography using 2% methanol DCM mixture as eluent toafford tert-butyl4-[4-(2-oxo-1H-benzo[cd]indole-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylate2 (1.5 g, 3.29 mmol, 73.83% yield) as greenish yellow solid. LC MS: ES+447.2.

Step 2: Synthesis of6-(1-(piperidin-4-yl)-1H-pyrazole-4-carbonyl)benzo[cd]indol-2-one;hydrochloride (3): Dioxane (5 mL) was added to tert-butyl4-[4-(2-oxo-1H-benzo[cd]indole-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylate2 (1.5 g, 3.36 mmol) in a single neck 100 mL round bottom flask to makea colloidal suspension. 4 M HCl in Dioxane (10 mL) was added to thesuspension and stirred for 3 h at room temperature under inertatmosphere. The reaction progression was monitored through TLC. Aftercompletion of the reaction dioxane was evaporated under reduced pressureand the crude compound was washed with diethyl ether to remove the nonpolar impurities. The combined compound and ether part was kept for sometime to allow the complete precipitation process. The supernatant etherpart was transferred to another conical flask and the settled purecompound was dried under reduced pressure to afford6-[1-(4-piperidyl)pyrazole-4-carbonyl]-1H-benzo[cd]indol-2-one;hydrochloride 3 (1.30 g, 3.04 mmol, 90.44% yield) as greenish solid. LCMS: ES+ 347.3.

Step 3: Synthesis of6-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazole-4-carbonyl)benzo[cd]indol-2-one(5): To a stirred solution of6-[1-(4-piperidyl)pyrazole-4-carbonyl]-1H-benzo[cd]indol-2-one;hydrochloride 3 (1.2 g, 3.13 mmol) in DMF (10 mL),N-ethyl-N-isopropyl-propan-2-amine (1.62 g, 12.54 mmol, 2.18 mL) wasadded under nitrogen atmosphere and at 0° C. The combined reactionmixture was stirred for 5 mins at the same temperature.1-methylcyclobutanecarboxylic acid 4 (393.55 mg, 3.45 mmol) and HATU(1.79 g, 4.70 mmol) were added to the reaction mixture. The combinedreaction mixture was stirred for 16 hours at room temperature. Thereaction progression was monitored through TLC. After completion of thereaction ethyl acetate was added to the reaction mixture. The organiclayer was washed with cold water and brine solution to remove DMF. Theethyl acetate layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purifiedthrough column chromatography using 100-200 mesh silica gel and 3%methanol DCM as eluent to afford6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazole-4-carbonyl]-1H-benzo[cd]indol-2-one5 (1 g, 2.21 mmol, 70.66% yield) as yellowish solid. LC MS: ES+ 443.3.

Step 4: Synthesis of6-(hydroxy(l-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2-one(6): To a stirred solution of6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazole-4-carbonyl]-1H-benzo[cd]indol-2-one5 (1 g, 2.26 mmol) in solvent mixture (Methanol (10 mL) and THF (10 mL))at 0° C., Sodium borohydride (384.73 mg, 10.17 mmol, 359.56 uL) wasadded portion wise in the reaction mixture. The reaction mixture wasstirred for 16 h at room temperature. The reaction progression wasmonitored through TLC. After completion of the reaction the solventmixture was concentrated under reduced pressure. Ethyl acetate was addedto the reaction mixture and washed with water. The organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The crude product was purified through column chromatographyusing 3% methanol DCM as eluent and 100-200 mesh silica gel asstationary phase to afford6-[hydroxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one6 (1 g, 2.20 mmol, 97.56% yield) as yellow solid. LCMS: ES+[M-OH]:427.3.

Step 5: Synthesis of6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)((trimethylsilyl)oxy)methyl)benzo[cd]indol-2-one(7): To a stirred solution of6-[hydroxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one6 (1 g, 2.25 mmol) in DMF (7 mL), Imidazole (459.44 mg, 6.75 mmol) wasadded at inert condition. The reaction mixture was stirred at roomtemperature for 5 mins. Chlorotrimethylsilane, 98+% (488.80 mg, 4.50mmol, 571.03 uL) was added drop wise in the reaction mixture at roomtemperature. The reaction mixture was stirred at the same temperaturefor 1 h. Reaction progression was monitored through TLC. Aftercompletion of the reaction ethyl acetate was added to the reactionmixture. The combined organic layer was washed with cold water and brineto remove DMF. the ethyl acetate part was dried over sodium sulfate andconcentrated under reduced pressure. The crude product was purifiedthrough column chromatography using 100-200 mesh silica gel and 2%methanol DCM mixture as eluent to afford6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]-trimethylsilyl oxy-methyl]-1H-benzo[cd]indol-2-one 7 (705 mg, 1.34 mmol, 59.44%yield) as yellow solid. LC MS: ES+[M-OTMS]: 427.4.

Step 6: Synthesis of6-[azido-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(8): To a stirred solution of6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]-trimethylsilyloxy-methyl]-1H-benzo[cd]indol-2-one7 (700 mg, 1.35 mmol) in DCM (7 mL), Trimethylsilyl azide, 94% (171.69mg, 1.49 mmol, 196.89 uL) was added under argon atmosphere. After that,trichloroiron (10.99 mg, 67.74 umol) was added to the reaction mixture.The combined reaction mixture was stirred for 2 h. The reactionprogression was monitored through TLC. After completion of the reactionethyl acetate was added to the reaction mixture. The organic layer waswashed with water. The organic layer was dried over sodium sulfate andconcentrated under reduced pressure to afford6-[azido-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one8 (600 mg, 1.25 mmol, 92.44% yield, 98% purity) as yellow solid. LCMS:ES+[M-N₃]: 427.4.

Step 7: Synthesis of6-(amino(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2-one(9):6-[azido-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one8 (450 mg, 958.39 umol) and Triphenylphosphine (377.06 mg, 1.44 mmol)was dissolved intoluene, THF mixture (1:1) and Water (0.5 mL) was addedto it. The combine reaction mixture was placed on a preheated oil bath(80° C.) for 14 h. After completion of the reaction the crude reactionmixture was concentrated under vacuum and ethyl acetate was added to it.The ethyl acetate layer was washed with water and the organic layer wasdried over sodium sulfate and filtered. The organic layer wasconcentrated under reduced pressure. The crude product was washed with20% ethyl acetate hexane to eliminate triphenylphosphine oxide and otherimpurities to get the desired6-[amino-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one9 (350 mg, 773.32 umol, 80.69%) as yellow solid. LCMS: ES+[M-NH₂]:427.5.

Step 8: Synthesis of3-(6-(amino(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione: To a stirred solution of6-[amino-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one9 (100 mg, 225.46 umol) in THF (6 mL) Sodium hydride (in oil dispersion)60% dispersion in mineral oil (86.39 mg, 2.25 mmol, 60% purity) wasadded at 0° C. under inert atmosphere the reaction mixture was stirredfor 10 mins at 0° C. Further the reaction mixture was stirred for 10mins at room temperature. Portion wise 3-bromopiperidine-2,6-dione 10(216.45 mg, 1.13 mmol) was added to the reaction mixture and afteraddition the reaction was stirred for another 10 mins at roomtemperature. The combined reaction mixture was placed in a preheated oilbath (80° C.) and reflux for 1 h. After 1 h ethyl acetate was added tothe reaction mixture and the combined reaction mixture was washed withwater. The organic layer was dried over sodium sulfate and concentratedunder reduced pressure. The crude product was purified through reversephase HPLC to afford3-[6-[amino-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 153 (15.0 mg, 26.25 umol, 11.64% yield) as yellow solid. ¹H NMR(400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.46-8.42 (m, 1H), 8.02 (d, J=6.6Hz, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.62-7.56 (m, 2H), 7.31 (s, 1H), 7.08(d, J=7.12, 1H), 5.68 (s, 1H), 5.42-5.40 (m, 1H), 4.35 (brs, 1H),4.27-4.26 (m, 1H), 3.58-3.57 (m, 1H), 3.02-2.89 (m, 2H), 2.75-2.60 (m,2H), 2.38-2.29 (m, 2H), 2.06-2.04 (m, 1H), 1.91-1.86 (m, 4H), 1.75-1.59(m, 5H), 1.31 (s, 3H), LC MS: ES− [M−H]: 553.2.

Example 68. Synthesis of tert-butyl4-(4-(amino(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Compound 154)

Step 1: Synthesis of tert-butyl4-(4-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)((trimethylsilyl)oxy)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(2): To a stirred solution tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate1 (1.8 g, 4.01 mmol) in DMF, Imidazole (819.64 mg, 12.04 mmol) wasadded. The combined reaction mixture was stirred for 5 minutes undernitrogen atmosphere at room temperature. Chlorotrimethylsilane, 98+%(872.02 mg, 8.03 mmol, 1.02 mL) was added drop wise to the reactionmixture at room temperature. After addition, the combined reactionmixture was stirred for 1 h. The reaction progression was monitoredthrough TLC. The reaction was quenched with water and ethyl acetate. Theorganic layer was washed with ice cold water followed by brine solutionto remove DMF. The organic layer was dried over sodium sulfate andfiltered. The organic layer was concentrated under reduced pressure. Thecrude product was purified with 40%-50% ethyl acetate and hexane toafford tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)-trimethylsilyloxy-methyl]pyrazol-1-yl]piperidine-1-carboxylate2 (1 g, 1.82 mmol, 45.46% yield) as yellow solid. LCMS: ES+[M-OTMS]:431.5.

Step 2: Synthesis of tert-butyl4-(4-(azido(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(3):tert-butyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)-trimethylsilyloxy-methyl]pyrazol-1-yl]piperidine-1carboxylate 2 (1 g, 1.92 mmol) and Trimethylsilyl azide, 94% (243.39 mg,2.11 mmol, 279.12 uL) were dissolved in DCM under argon atmosphere.Ferric Chloride (15.58 mg, 96.03 umol) was added to the reaction mixtureand stirred for 2 h at room temperature. After completion of thereaction, ethyl acetate was added to the reaction mixture and washedwith water. The organic layer was dried over sodium sulfate, filteredand concentrated under reduced pressure. The crude product was purifiedthrough column chromatography using 25% ethyl acetate and DCM mixture toafford tert-butyl4-[4-[azido-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate3 (700 mg, 1.40 mmol, 73.12% yield) as yellow solid. LCMS: ES+[M-OTMS]:431.3.

Step 3: Synthesis of tert-butyl4-(4-(amino(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(4):tert-butyl-4-[4-[azido-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate3 (300 mg, 633.55 umol) was dissolved in THF (3 mL) Toluene (3 mL)mixture (1:1) in a two neck 50 mL round bottom flask. Triphenylphosphine(249.26 mg, 950.32 umol) was added to the reaction mixture. After thatfew drops of Water (0.200 mL) was added to it. The combined reactionmixture was placed on a preheated oil bath (80° C.) with a refluxcondenser. The reaction mixture was heated at the same temperature for12 h. After completion of the reaction the reaction mixture wasconcentrated under reduced pressure and diluted with ethyl acetate.Ethyl acetate layer was washed with water. The organic layer was driedover sodium sulfate and filtered. The ethyl acetate part wasconcentrated under reduced pressure to get the crude product. The crudeproduct was washed with 20% ethyl acetate hexane mixture to removeexcess triphenylphosphine and triphenylphosphine oxide to affordtert-butyl4-[4-[amino-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate4 (250 mg, 335.17 umol, 52.90% yield) as yellow solid. LC MS: ES+[M−N₃]: 431.2.

Step 4: Synthesis of tert-butyl4-(4-(amino(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:To a stirred solution of tert-butyl4-[4-[amino-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate4 (200 mg, 446.90 umol) in THF (6 mL) Sodium hydride (in oil dispersion)60% dispersion in mineral oil (171.24 mg, 4.47 mmol, 60% purity) wasadded at 0° C. under inert atmosphere. The reaction mixture was stirredfor 10 mins at 0° C. Further the reaction mixture was stirred for 10mins at room temperature. Portion wise 3-bromopiperidine-2,6-dione 5(429.05 mg, 2.23 mmol) was added to the reaction mixture and afteraddition the reaction mixture was stirred for another 10 mins at roomtemperature. The combined reaction mixture was placed in a preheated oilbath (80° C.) and reflux for 1 h. After 1 h, ethyl acetate was added tothe reaction mixture and the combined reaction mixture was washed withwater. The organic layer was dried over sodium sulfate and concentratedunder reduced pressure. The crude product was purified with reversephase HPLC to afford tert-butyl4-[4-[amino-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylateCompound 154 (22 mg, 38.91 umol, 8.71% yield). ¹H NMR (400 MHz,DMSO-d6): δ 11.11 (s, 1H), 8.48-8.46 (m, 1H), 8.05 (d, J=6.88 Hz, 1H),7.78 (t, J=7.56 Hz, 1H), 7.63 (d, J=7.28 Hz, 1H), 7.58 (d, J=4.80 Hz,1H), 7.32 (s, 1H), 7.10 (d, J=7.16 Hz, 1H), 5.70 (s, 1H), 5.45-5.43 (m,1H), 4.23-4.20 (m, 1H), 3.96-3.95 (m, 2H), 2.98-2.74 (m, 4H), 2.67-2.63(m, 1H), 2.09-2.07 (m, 1H), 1.89-1.88 (m, 2H), 1.69-1.66 (m, 2H), 1.39(s, 9H); LC MS: ES− [M-NH₂]: 542.2.

Example 69. Synthesis of3-[6-[[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 155)

Step 1: Synthesis of2-[[4-(chloromethyl)phenyl]methyl]-3,4-dihydro-1H-isoquinoline: To thestirred solution of 1,2,3,4-tetrahydroisoquinoline 2 (1 g, 7.51 mmol,1.00 mL) in Acetone (10 mL) Potassium carbonate, anhydrous, 99% (1.04 g,7.51 mmol, 453.14 uL) was added and stirred at 50° C. for 20 minutesfollowed by the addition of 1,4-bis(chloromethyl)benzene 1 (1.31 g, 7.51mmol, 925.58 uL). Resulting solution was further heated at sametemperature for 16 hr. After formation of desired product, as evidencedfrom LCMS, volatiles were removed and redissolved in ethyl acetate.Organic portion was washed with water/brine and separated, dried oversodium sulfate and concentrated. Crude Residue was purified by columnchromatography using 30% EtOAc-Hexane to afford2-[[4-(chloromethyl)phenyl]methyl]-3,4-dihydro-1H-isoquinoline 3 (750mg, 2.65 mmol, 35.28% yield, 96% purity) white gum. LC MS: ES+ 272.2.

Step 2: Synthesis of6-[[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of2-[[4-(chloromethyl)phenyl]methyl]-3,4-dihydro-1H-isoquinoline 3 (400mg, 1.47 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one4 (868.75 mg, 2.94 mmol) in ethanol (2.5 mL) and Toluene (5 mL) wasadded Potassium phosphate tribasic anhydrous (937.23 mg, 4.42 mmol) andthe reaction mass was degaussed under Argon atmosphere over 10 minutes.Then Tri-o-Tolyl phosphine (89.59 mg, 294.35 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (134.77 mg, 147.18umol) was added to this reaction mass and heated the resultant reactionmixture 90° C. over night. TLC shows consumption of starting material.Then the reaction mixture was filtered through sintered funnel usingcelite bed and the reaction mixture was diluted with ethyl acetate andwashed with water. The organic part was dried over Na₂SO₄ and filtered.The reaction mix was evaporated under reduced pressure, the crude waspurified by combi-flash to get the pure compound6-[[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one5 (160 mg, 375.77 umol, 25.53% yield, 95% purity) as light yellow solid.LC MS: ES+ 405.4.

Step 3: Synthesis of3-[6-[[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To the stirred solution of6-[[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one5 (159.21 mg, 393.59 umol) in THF (3 mL) was added Sodium hydride (inoil dispersion) 60% dispersion in mineral oil (150.81 mg, 3.94 mmol, 60%purity) at cold condition and the reaction mixture was stirred at roomtemperature for 10 minutes followed by the addition of3-bromopiperidine-2,6-dione 6 (377.86 mg, 1.97 mmol) portion wise. Itwas then stirred at room temperature for 10 minutes and heated at 70° C.for 30 minutes. TLC was checked which showed almost complete consumptionof the starting material and formation of the desired spot. The reactionmixture was diluted with ethyl acetate, washed with cold water and theorganic fraction was separated. It was then dried over anhydrous sodiumsulphate and evaporated under reduced pressure to obtain the crude whichwas washed with ether and pentane to afford3-[6-[[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 155 (125.0 mg, 234.56 umol, 59.59% yield, 96.75% purity) asyellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.33 (d,J=8.24 Hz, 1H), 8.07 (d, J=6.84 Hz, 1H), 7.80 (t, J=7.54 Hz, 1H), 7.41(d, J=7.32 Hz, 1H), 7.25 (s, 4H), 7.12-7.07 (m, 4H), 6.98-6.95 (m, 1H),5.44 (dd, J=12.36, 4.36 Hz, 1H), 4.38 (s, 2H), 3.56 (s, 2H), 3.48 (s,2H), 2.95-2.90 (m, 1H), 2.78-2.76 (m, 3H), 2.70-2.61 (m, 3H), 2.10-2.07(m, 1H)LC MS: ES+ 516.5.

Example 70. Synthesis of3-[6-[[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 156)

Step 1: Synthesis of8-[[4-(chloromethyl)phenyl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane: Tothe stirred solution of 3-oxa-8-azabicyclo[3.2.1]octane; hydrochloride 2(1.00 g, 6.68 mmol, 1.00 mL) in Acetone (10 mL) added DIPEA (863.82 mg,6.68 mmol, 1.16 mL) to basified, then Potassium carbonate, anhydrous,99% (923.75 mg, 6.68 mmol, 403.39 uL) was added and stirred at 50° C.for 20 minutes followed by the addition of 1,4-bis(chloromethyl)benzene1 (1.17 g, 6.68 mmol, 823.95 uL). Resulting solution was further heatedat same temperature for 16 hours. After formation of desired product, asevidenced from LCMS, volatiles were removed and redissolved in ethylacetate. Organic portion was washed with water/brine and separated,dried over sodium sulfate and concentrated under reduced pressure. Crudemass was purified by column chromatography using 1-2% MeOH-DCM as eluentto afford8-[[4-(chloromethyl)phenyl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane 3(750 mg, 2.83 mmol, 42.34% yield, 95% purity) as a white gum. LC MS: ES+251.8

Step 2: Synthesis of6-[[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of8-[[4-(chloromethyl)phenyl]methyl]-3-oxa-8-azabicyclo[3.2.1]octane 3(400.00 mg, 1.59 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one4 (937.88 mg, 3.18 mmol) in ethanol (2.5 mL) and Toluene (5 mL) wasadded Potassium phosphate tribasic anhydrous (1.01 g, 4.77 mmol) and thereaction mass was degassed under argon atmosphere over 10 minutes. ThenTri-o-Tolyl phosphine (96.72 mg, 317.77 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (145.50 mg, 158.89umol) was added to this reaction mass and heated the resultant reactionmixture 90° C. over night. Check TLC shows consumption of SM. Then thereaction mix was filtered through sintered funnel using celite bed andthe reaction mix was diluted with ethyl acetate and washed with water.The organic part was dried over Na₂SO₄ and filtered. The reaction mixwas evaporated under reduced pressure, the crude was purified bycombi-flash to get the pure compound6-[[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one5 (250 mg, 637.24 umol, 40.11% yield, 98% purity) as light yellow solid.LC MS: ES+ 385.3.

Step 3: Synthesis of3-[6-[[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To the stirred solution of6-[[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one5 (250 mg, 650.25 umol) in THF (3 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (249.15 mg, 6.50 mmol, 60%purity) at cold condition and the reaction mixture was stirred at roomtemperature for 10 minutes followed by the addition of3-bromopiperidine-2,6-dione 6 (624.27 mg, 3.25 mmol) portion wise. Itwas then stirred at room temperature for 10 minutes and heated at 70° C.for 30 minutes. TLC was checked which showed almost complete consumptionof the starting material and formation of the desired spot. The reactionmixture was diluted with ethyl acetate, washed with cold water and theorganic fraction was separated. It was then dried over anhydrous sodiumsulphate and evaporated under reduced pressure to obtain the crude whichwas washed with ether and pentane to afford3-[6-[[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 156 (145.0 mg, 287.91 umol, 44.28% yield, 98.40% purity) asyellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.33 (d, J=8.2Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 7.40 (d,J=7.24 Hz, 1H), 7.25-7.21 (m, 4H), 7.10 (d, J=7.24 Hz, 1H), 5.44 (dd,J=12.52, 5.0 Hz, 1H), 4.36 (s, 2H), 3.49-3.46 (m, 2H), 3.37-3.29 (m,4H), 2.99-2.90 (m, 3H), 2.80-2.62 (m, 2H), 2.10-2.07 (m, 1H), 1.91-1.88(m, 2H), 1.71-1.69 (m, 2H) LC MS: ES+ 496.5.

Example 71. Synthesis of3-[6-[[4-[[4-[(4-fluorophenyl)methyl]-1-piperidyl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 157)

Step 1: Synthesis of1-[[4-(chloromethyl)phenyl]methyl]-4-[(4-fluorophenyl)methyl]piperidine:To a stirred solution of 4-[(4-fluorophenyl)methyl]piperidine 2 (550 mg,2.85 mmol) in DMF (5 mL) was added N,N-Diisopropylethylamine (1.10 g,8.54 mmol, 1.49 mL) and stirred for 5 min. Then1,4-bis(chloromethyl)benzene 1 (498.19 mg, 2.85 mmol) was added and thereaction was heated at 60° C. for 16 hours. After completion of thereaction (monitored by TLC), the reaction mixture was diluted with ethylacetate and washed with water and brine, dried over sodium sulfate andconcentrated. Crude material was purified by column chromatography(100-200 silica, 25-30% EtOAc in hexane) to afford1-[[4-(chloromethyl)phenyl]methyl]-4-[(4-fluorophenyl)methyl]piperidine3 (120 mg, 343.52 umol, 12.07% yield, 95% purity) as light yellow oil.LC MS: ES+ 332.18.

Step 2: Synthesis of6-[[4-[[4-[(4-fluorophenyl)methyl]-1-piperidyl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of1-[[4-(chloromethyl)phenyl]methyl]-4-[(4-fluorophenyl)methyl]piperidine3 (150 mg, 452.01 umol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one4 (266.81 mg, 904.01 umol) in ethanol (2 mL) and Toluene (4 mL) wasadded Potassium phosphate tribasic anhydrous (287.84 mg, 1.36 mmol) andthe reaction mass was degassed under argon atmosphere over 10 minutes.Then Tri-o-Tolyl phosphine (27.52 mg, 90.40 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (41.39 mg, 45.20umol) was added to this reaction mass and heated the resultant reactionmixture 90° C. over night. Then the reaction mixture was filteredthrough sintered funnel using celite bed and the reaction mix wasdiluted with ethyl acetate and washed with water. The organic part wasdried over Na₂SO₄ and evaporated under reduced pressure. Crude materialwas purified by combi-flash to get the pure compound6-[[4-[[4-[(4-fluorophenyl)methyl]-1-piperidyl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one5 (160 mg, 327.18 umol, 72.38% yield, 95% purity) as light yellow solid.LC MS: ES+ 465.3.

Step 3: Synthesis of3-[6-[[4-[[4-[(4-fluorophenyl)methyl]-1-piperidyl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To the stirred solution of6-[[4-[[4-[(4-fluorophenyl)methyl]-1-piperidyl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one5 (180 mg, 387.45 umol) in THF (5 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (148.46 mg, 3.87 mmol, 60%purity) at cold condition and the reaction mixture was stirred at roomtemperature for 10 minutes followed by the addition of3-bromopiperidine-2,6-dione 6 (371.98 mg, 1.94 mmol) portion wise. Itwas then stirred at room temperature for 10 minutes and heated at 70° C.for 30 minutes. TLC was checked which showed almost complete consumptionof the starting material and formation of the desired spot. The reactionmixture was diluted with ethyl acetate, washed with cold water and theorganic fraction was separated. It was then dried over anhydrous sodiumsulphate and evaporated under reduced pressure to obtain the crude masswhich was purified by Prep TLC using 60% EtOAc-DCM as eluent to afford3-[6-[[4-[[4-[(4-fluorophenyl)methyl]-1-piperidyl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 157 (25.0 mg, 42.76 umol, 11.04% yield, 98.47% purity) asyellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.32 (d,J=8.24 Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.56 Hz, 1H), 7.39(d, J=7.36 Hz, 1H), 7.21-7.04 (m, 9H), 5.47-5.40 (m, 1H), 4.37 (s, 2H),3.29 (s, 2H), 2.90-2.80 (m, 1H), 2.76-2.67 (m, 4H), 2.46-2.44 (m, 2H),2.09-2.07 (m, 1H), 1.80-1.70 (m, 2H), 1.47-1.45 (m, 3H), 1.14-1.11 (m,2H); LC MS: ES+ 476.5.

Example 72. Synthesis of3-[6-[[4-[(4-tert-butyl-1-piperidyl)methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 158)

Step 1: Synthesis of4-tert-butyl-1-[[4-(chloromethyl)phenyl]methyl]piperidine: To a stirredsolution of 4-tert-butylpiperidine 2 (550 mg, 3.89 mmol) in DMF (5 mL)was added N,N-Diisopropylethylamine (1.51 g, 11.68 mmol, 2.03 mL) andstirred for 5 min. Then 1,4-bis(chloromethyl)benzene 1 (681.61 mg, 3.89mmol) was added and the reaction was heated at 60° C. for 16 hours.After completion of the reaction (monitored by TLC), the reactionmixture was diluted with ethyl acetate and washed with water and brine,dried over sodium sulfate and concentrated. The crude was purified bycolumn chromatography (100-200 silica, 25-30% EtOAc in hexane) to afford4-tert-butyl-1-[[4-(chloromethyl)phenyl]methyl]piperidine 3 (170 mg,577.10 umol, 14.82% yield, 95% purity) as yellow oil. LC MS: ES+ 280.2.

Step 2: Synthesis of6-[[4-[(4-tert-butyl-1-piperidyl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of4-tert-butyl-1-[[4-(chloromethyl)phenyl]methyl]piperidine 3 (170 mg,607.47 umol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one4 (358.58 mg, 1.21 mmol) in ethanol (2 mL) and Toluene (4 mL) was addedPotassium phosphate tribasic anhydrous (386.85 mg, 1.82 mmol) and thereaction mass was degassed under argon atmosphere over 10 minutes. ThenTri-o-Tolyl phosphine (36.98 mg, 121.49 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (55.63 mg, 60.75umol) was added to this reaction mass and heated the resultant reactionmixture 90° C. over night. Check TLC shows consumption of SM. Then thereaction mix was filtered through sintered funnel using celite bed andthe reaction mix was diluted with ethyl acetate and washed with water.The organic part was dried over Na₂SO₄ and filtered. The reaction mixwas evaporated under reduced pressure, the crude was purified bycombi-flash to get the pure compound6-[[4-[(4-tert-butyl-1-piperidyl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one5 (100 mg, 230.27 umol, 37.91% yield, 95% purity) as light yellow solid.LC MS; ES+ 413.0.

Step 3: Synthesis of3-[6-[[4-[(4-tert-butyl-1-piperidyl)methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To the stirred solution of6-[[4-[(4-tert-butyl-1-piperidyl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one5 (100 mg, 242.39 umol) in THF (5 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (92.87 mg, 2.42 mmol, 60%purity) at cold condition and the reaction mixture was stirred at roomtemperature for 10 minutes followed by the addition of3-bromopiperidine-2,6-dione 6 (232.70 mg, 1.21 mmol) portion wise. Itwas then stirred at room temperature for 10 minutes and heated at 70° C.for 30 minutes. The reaction mixture was diluted with ethyl acetate,washed with cold water and the organic fraction was separated. It wasthen dried over anhydrous sodium sulphate and evaporated under reducedpressure to obtain the crude mass which was purified by Prep TLC using60% EtOAc-DCM as eluent to afford3-[6-[[4-[(4-tert-butyl-1-piperidyl)methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 158 (45.0 mg, 81.64 umol, 33.68% yield, 95% purity) as yellowsolid. ¹H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.32 (d, J=8.20 Hz,1H), 8.07 (d, J=6.96 Hz, 1H), 7.80 (t, J=7.56 Hz, 1H), 7.40 (d, J=7.32Hz, 1H), 7.23-7.17 (m, 4H), 7.10 (d, J=7.32 Hz, 1H), 5.46-5.41 (m, 1H),4.37 (s, 2H), 3.29 (s, 2H), 2.95-2.90 (m, 1H), 2.80-2.73 (m, 2H),2.66-2.62 (m, 2H), 2.10-2.07 (m, 1H), 1.80-1.70 (m, 2H), 1.55-1.52 (m,2H), 1.17-1.14 (m, 2H), 0.95-0.85 (m, 1H), 0.79 (s, 9H); LC MS: ES+524.6.

Example 73. Synthesis of Chiral Separation of3-(2-Oxo-6-{4-[4-(2,2,2-trifluoro-ethanesulfonyl)-piperazin-1-ylmethyl]-benzyl}-2H-benzo[cd]indol-1-yl)-piperidine-2,6-dione(Compound 159) and3-(2-Oxo-6-{4-[4-(2,2,2-trifluoro-ethanesulfonyl)-piperazin-1-ylmethyl]-benzyl}-2H-benzo[cd]indol-1-yl)-piperidine-2,6-dione(Compound 160)

Step 1: Chiral Separation: 550 mg of Compound 109 was separated bynormal phase preparative Chiral-HPLC method to afford3-[2-oxo-6-[[4-[[4-(2,2,2-trifluoroethylsulfonyl)piperazin-1yl]methyl]phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 159 (160.0 mg, 257.92 umol, 28.82% yield, 99.08% purity, %ee-100) and3-[2-oxo-6-[[4-[[4-(2,2,2-trifluoroethylsulfonyl)piperazin-1yl]methyl]phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 160 (165.0 mg, 266.17 umol, 29.74% yield, 99.15% purity, %ee-100) both as yellow solid. ¹H NMR (d6-DMSO, 400 MHZ) d 11.12 (s, 1H),8.32 (d, J=8.36, 1H), 8.07 (d, J=6.96, 1H), 7.80 (t, J=7.6, 1H), 7.40(d, J=7.4, 1H), 7.25 (d, J=7.84, 2H), 7.19 (d, J=7.84, 2H), 7.10 (d,J=7.08, 1H), 5.44-5.43 (dd, J=12.8, 5.2 Hz, 1H), 4.50-4.43 (m, 2H), 4.37(s, 2H), 3.44 (s, 2H), 3.18 (br s, 4H), 2.94 (m, 1H), 2.76-2.73 (m, 1H),2.66-2.62 (m, 1H), 2.39 (br s, 4H), 2.09-2.08 (m, 1H); LC MS: ES+ 615.1.

Example 74. Synthesis of3-(2-Oxo-6-{4-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-ylmethyl]-benzyl}-2H-benzo[cd]indol-1-yl)-piperidine-2,6-dione(Compound 161)

Step 1: Synthesis of1-(4-Chloromethyl-benzyl)-4-(2,2,2-trifluoro-ethyl)-piperazine: To astirred solution of 1-(2,2,2-trifluoroethyl)piperazine 1 (500.00 mg,2.97 mmol) in DMF (5 mL) was added N,N-Diisopropylethylamine (1.15 g,8.92 mmol, 1.55 mL) and stirred for 5 minutes. Then1,4-bis(chloromethyl)benzene 2 (520.50 mg, 2.97 mmol) was added and thereaction was heated at 60° C. for 16 hours. After completion of thereaction (monitored by TLC), the reaction mixture was diluted with ethylacetate and washed with water and brine, dried over sodium sulfate andconcentrated. The crude was purified by flash chromatography (0-5% MeOHin DCM) to afford1-[[4-(chloromethyl)phenyl]methyl]-4-(2,2,2-trifluoroethyl)piperidine 3(300.0 mg, 902.65 umol, 30.36% yield, 92% purity) as yellow liquid. LCMS: ES+ 306.8.

Step 2: Synthesis of6-{4-[4-(2,2,2-Trifluoro-ethyl)-piperazin-1-ylmethyl]-benzyl}-1H-benzo[cd]indol-2-one:To a stirred solution of1-[[4-(chloromethyl)phenyl]methyl]-4-(2,2,2-trifluoroethyl)piperazine 3(300.0 mg, 977.98 umol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one4 (577.28 mg, 1.96 mmol) in Ethanol (2 mL) and Toluene (4 mL) was addedPotassium phosphate tribasic anhydrous (622.79 mg, 2.93 mmol) and thereaction mass was degassed under argon atmosphere for 10 minutes. ThenTri-o-Tolyl phosphine (59.53 mg, 195.60 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (89.56 mg, 97.80umol) was added to this reaction mass and heated at 90° C. 16 hours. Thereaction mixture was filtered through sintered funnel using celite bedand the filtrate was evaporated under reduced pressure which waspurified by flash chromatography using 0-5% MeOH-DCM to afford6-[[4-[[4-(2,2,2-trifluoroethyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one5 (177.0 mg, 397.12 umol, 40.61% yield, 98.6% purity) as yellow solid.LC MS: ES+ 440.5.

Step 3: Synthesis of3-(2-Oxo-6-{4-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-ylmethyl]-benzyl}-2H-benzo[cd]indol-1-yl)-piperidine-2,6-dione:To the stirred solution of6-[[4-[[4-(2,2,2-trifluoroethyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one5 (177.0 mg, 402.76 umol) in THF (10 mL) was added Sodium hydride (inoil dispersion) 60% dispersion in mineral oil (185.19 mg, 4.83 mmol, 60%purity) at cold condition and the reaction mixture was stirred at roomtemperature for 10 minutes followed by the addition of3-bromopiperidine-2,6-dione 6 (386.67 mg, 2.01 mmol) portion wise. Itwas then stirred at room temperature for 10 minutes and heated at 70° C.for 30 minutes. After completion of reaction (monitored by TLC) thereaction mixture was diluted with ethyl acetate, washed with cold waterand the organic fraction was separated. It was then dried over anhydroussodium sulphate and evaporated under reduced pressure to obtain thecrude which was washed with ether and pentane to afford3-[2-oxo-6-[[4-[[4-(2,2,2-trifluoroethyl)piperazin-1-yl]methyl]phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 161 (120.0 mg, 217.96 umol, 54.12% yield, 100.00% purity) asyellow solid. ¹H NMR (d6-DMSO, 400 MHZ) d 11.12 (s, 1H), 8.32 (d,J=8.16, 1H), 8.07 (d, J=6.92, 1H), 7.80 (t, J=7.62, 1H), 7.39 (d,J=7.16, 1H), 7.22 (d, J=7.72, 2H), 7.16 (d, J=7.72, 2H), 7.10 (d,J=7.24, 1H), 5.46-5.43 (m, 1H), 4.37 (s, 2H), 3.36 (s, 2H), 3.14-3.06(m, 2H), 2.98-2.90 (m, 1H), 2.79-2.73 (m, 1H), 2.66-2.62 (m, 1H),2.56-2.49 (br s, 4H), 2.31 (br s, 4H), 2.10-2.07 (m, 1H); LC MS: ES+551.5.

Example 75. Synthesis of3-[6-[(1-cyclohexylpyrazol-4-yl)methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 162)

Step 1: Synthesis of cyclohexyl methanesulfonate: To a stirred solutionof cyclohexanol 1 (2 g, 19.97 mmol, 2.08 mL) in DCM (20 mL), was addedTriethylamine (4.45 g, 43.93 mmol, 6.12 mL), cooled the reaction mixtureto 0° C. followed by drop wise addition of Methanesulfonyl chloride(2.74 g, 23.96 mmol, 1.85 mL) then reaction mixture was heated to 25° C.for 2 hours. After completion of SM, reaction mass was diluted withwater and extracted with DCM, washed with saturated solution of NaHCO₃,brine, dried over anhydrous sodium sulphate and evaporate under reducedpressure to give the crude compound cyclohexyl methanesulfonate 2 (3.5g, 19.64 mmol, 98.33% yield, 100% purity) as orange liquid, which wasused in next step without further purification. ¹H NMR (400 MHz, CDCl₃)δ 4.72-4.65 (m, 1H), 2.99 (s, 3H), 1.96-1.95 (m, 2H), 1.78-1.75 (m, 2H),1.67-1.59 (m, 2H), 1.55-1.50 (m, 1H), 1.42-1.41 (m, 2H), 1.34-1.32 (m,1H);

Step 2: Synthesis of 1-cyclohexylpyrazole-4-carbaldehyde: To the stirredsolution of 1H-pyrazole-4-carbaldehyde 3 (2 g, 20.81 mmol) andcyclohexyl methanesulfonate 2 (3.71 g, 20.81 mmol) in DMF (20 mL) wasadded Cesium carbonate (13.56 g, 41.63 mmol) and the reaction mixturewas heated at 80° C. for 16 hours. TLC was checked which showed completeconsumption of the starting material along with the formation of thedesired spot. The reaction mixture was diluted with ethyl acetate,washed with water and the organic fraction was separated. It was thendried over anhydrous sodium sulphate and evaporated under reducedpressure to obtain the crude which was purified by flash chromatographyusing 0-20% ethyl acetate-hexane to afford1-cyclohexylpyrazole-4-carbaldehyde 4 (1.5 g, 8.33 mmol, 40.03% yield,99% purity) as a white semisolid. LC MS: ES+ 179.0.

Step 3: Synthesis of6-[(1-cyclohexylpyrazol-4-yl)-hydroxy-methyl]-1H-benzo one: To thestirred solution of 6-bromo-1H-benzo[cd]indol-2-one 5 (1.39 g, 5.61mmol) in THF (20 mL) was added Phenyl lithium, typically 1.9M indi-n-butyl ether (1.8 M, 3.12 mL) at −78° C. and the reaction wasstirred at the same temperature for 30 minutes followed by the additionof Butyl lithium (2.00 M, 3.09 mL) at −78° C. and after the addition wascomplete the temperature was allowed to increase to −40° C. and thereaction mixture was stirred at the same temperature for 30 minutesfollowed by the addition of 1-cyclohexylpyrazole-4-carbaldehyde 4 (1 g,5.61 mmol) in THF (10 mL) at −78° C. and then the reaction mixture wasallowed to warm to room temperature and was continued for 16 hours. Itwas quenched with saturated ammonium chloride solution, extracted withethyl acetate, washed with water, brine, dried over sodium sulphate andwas concentrated under reduced pressure. It was purified by comb flasheluting at 1% methanol in dichloromethane to afford6-[(1-cyclohexylpyrazol-4-yl)-hydroxy-methyl]-1H-benzo[cd]indol-2-one 6(280 mg, 773.40 umol, 13.78% yield, 95.96% purity) as brown solid. LCMS: ES+ 348.3.

Step 3: Synthesis of6-[(1-cyclohexylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one: To thestirred solution of6-[(1-cyclohexylpyrazol-4-yl)-hydroxy-methyl]-1H-benzo[cd]indol-2-one 6(280 mg, 805.97 umol) in DCE (5 mL) was added Triethylsilane (374.87 mg,3.22 mmol, 514.93 uL), Trifluoroacetic acid (735.17 mg, 6.45 mmol,496.74 uL) and the reaction mixture was heated at 80° C. for 2 hours.The reaction mixture was evaporated under reduced pressure to obtain thecrude compound which was purified by flash chromatography using 0-3%MeOH-DCM to afford6-[(1-cyclohexylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one 7 (160 mg,458.65 umol, 56.91% yield, 95% purity) as yellow solid. LC MS: ES+332.4.

Step 4: Synthesis of3-[6-[(1-cyclohexylpyrazol-4-yl)methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To the stirred solution of6-[(1-cyclohexylpyrazol-4-yl)methyl]-1H-benzo[cd]indol-2-one 7 (60 mg,181.04 umol) in DMF (2 mL) was added Sodium hydride (in oil dispersion)60% dispersion in mineral oil (13.87 mg, 362.09 umol, 60% purity) incold condition and the reaction mixture was heated at 60° C. for 1 hourfollowed by the addition of 3-bromopiperidine-2,6-dione 8 (34.76 mg,181.04 umol) and the reaction was continued at 60° C. for 4 hours withfurther addition of 3-bromopiperidine-2,6-dione 8 (34.76 mg, 181.04umol) and the reaction was continued for 16 hours at 70° C. The reactionmixture was quenched with cold water and EtOAc was added, layers wereseparated. The organic layer was washed with water, brine, dried overNa₂SO₄ and concentrated under reduced pressure to get crude mass whichwas purified by Prep TLC using 25% EtOAc-DCM as eluent to afford3-[6-[(1-cyclohexylpyrazol-4-yl)methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 162 (8 mg, 18.08 umol, 9.99% yield, 100% purity) as yellowsolid. ¹H NMR (d6-DMSO, 400 MHZ) d 11.11 (S, 1H), 8.37 (d, J=Hz, 1H),8.08 (d, J=8.08 Hz, 1H), 7.83 (t, J=7.38 Hz, 1H), 7.52 (s, 1H), 7.35 (d,J=7.28 Hz, 1H), 7.27 (s, 1H), 7.07 (d, J=7.24 Hz, 1H), 5.44-5.42 (m,1H), 4.17 (s, 2H), 4.01-3.99 (m, 1H), 2.98-2.90 (m, 1H), 2.79-2.72 (m,1H), 2.66-2.62 (m, 1H), 2.08-2.07 (m, 1H), 1.92-1.89 (m, 2H), 1.76-1.73(m, 2H), 1.62-1.59 (m, 3H), 1.37-1.30 (m, 2H), 1.25-1.20 (m, 1H); LC MS:ES+ 443.5.

Example 76. Synthesis of3-[6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]cyclopropyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 163) and3-[6-[1-[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]cyclopropyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 164)

Step 1: Synthesis of ethyl 2-bromoprop-2-enoate: To a stirred solutionof ethyl 2,3-dibromopropanoate 1 (9.9 g, 38.09 mmol, 5.53 mL) in THF (40mL) was cooled to 0° C. followed by drop wise addition of Triethylamine(3.85 g, 38.09 mmol, 5.31 mL), the reaction mixture was stirred for 8hours at room temperature. After completion of the reaction, Thereaction mixture was quenched water and EtOAc, layers were separated,the organic layer was washed with saturated solution of NaHCO₃, brine,dried over Na₂SO₄ and concentrated under vacuum pump to afford ethyl2-bromoprop-2-enoate 2 (5 g, 27.65 mmol, 72.60% yield, 99% purity) ascolourless liquid, which was used in next step without furtherpurification. 1H NMR (400 MHz, CDCl₃) δ 6.94 (s, 1H), 6.25 (s, 1H), 4.27(q, J=7.01 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).

Step 2: Synthesis of tert-butyl4-[4-(1-ethoxycarbonylvinyl)pyrazol-1-yl]piperidine-1-carboxylate: Tostirred a solution of ethyl 2-bromoprop-2-enoate 2 (3.8 g, 21.23 mmol)in THF/H2O (5 ml, 8:2), were added tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate3 (11.21 g, 29.72 mmol) and Potassium phosphate tribasic anhydrous(22.53 g, 106.14 mmol) under nitrogen atmosphere. Reaction mixture wasdegassed for 10 minutes using argon and was added Xphos palladacycle Gen3 (1.80 g, 2.12 mmol). Reaction mixture was heated to 60° C. for 16hours. After completion of reaction, quenched with water and extractedwith ethyl acetate (3×10 ml), organic layer concentrated under reducedpressure to afford tert-butyl4-[4-(1-ethoxycarbonylvinyl)pyrazol-1-yl]piperidine-1-carboxylate 4 (7g, 17.63 mmol, 83.05% yield, 88% purity) as gummy liquid which was usedin next step (immediately) without further purification. LC MS: ES+350.4.

Step 3: Synthesis of tert-butyl4-[4-(1-ethoxycarbonylcyclopropyl)pyrazol-1-yl]piperidine-1-carboxylate:To a stirred solution of (Me₃SOI)BLAHmethane; iodide (5.59 g, 25.41mmol) in DMSO (40 mL) was added Potassium tert-butoxide (2.38 g, 21.18mmol) at room temperature and stirred for 45 min at ambient temperature.Then a solution of tert-butyl4-[4-(1-ethoxycarbonylvinyl)pyrazol-1-yl]piperidine-1-carboxylate 4 (7.4g, 21.18 mmol) intoluene (20 ml) and DMSO (20 ml) was added over 3 min.The reaction mixture was heated at 50° C. for 16 hours. Reaction mixturecooled to RT washed by cold water. Aqueous layer was extracted withethyl acetate. Organic layer was dried over sodium sulphate,concentrated under reduced pressure. Crude material was purified bycombiflash chromatography at 10% EA/Hexane to afford tert-butyl4-[4-(1-ethoxycarbonylcyclopropyl)pyrazol-1-yl]piperidine-1-carboxylate5 (3.8 g, 10.35 mmol, 48.88% yield, 99% purity) as gummy liquid. LC MS:ES+ 364.1.

Step 4: Synthesis of1-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]cyclopropanecarboxylicacid: To a stirred solution of tert-butyl4-[4-(1-ethoxycarbonylcyclopropyl)pyrazol-1-yl]piperidine-1-carboxylate5 (3.8 g, 10.46 mmol) in THF (15 mL) (1:1) mixture was added Lithiumhydroxide, monohydrate (658.06 mg, 15.68 mmol, 435.80 uL) and stirredthe reaction mixture for 16 hours in 60° C. TLC showed un-reactedstarting material. A small pinch of KOH was added and the reactionmixture was further heated at 60° C. for 16 hours. The reaction mixturewas diluted with water and extracted with ethyl acetate; the aqueouslayer was acidified with 2 (N) HCl to pH-5-6 and extracted with 20%IPA-DCM. The organic layer was washed with brine solution, dried oversodium sulfate and concentrated to afford1-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]cyclopropanecarboxylic acid 6 (2.2 g, 6.49 mmol, 62.11% yield, 99% purity) as awhite solid. LC MS: ES+ 336.2.

Step 5: Synthesis of tert-butyl4-[4-[1-(1,3-dioxoisoindolin-2-yl)oxycarbonylcyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate:A round-bottom flask equipped with a stir bar was charged with1-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]cyclopropanecarboxylicacid 6 (1.27 g, 3.79 mmol), 2-hydroxyisoindoline-1,3-dione 7 (679.47 mg,4.17 mmol) and DMAP (46.26 mg, 378.66 umol). DCM (15 mL) was added(0.1-0.5 M) followed by N,N′-diisopropylmethanediimine (525.65 mg, 4.17mmol, 648.95 uL), and the mixture was allowed to stir vigorously for 2hours. The mixture was filtered over Celite and rinsed with additionalDCM. The solvent was removed under reduced pressure, and purification bycolumn chromatography using (20-25% EtOAc-Hexane) as eluent affordedtert-butyl4-[4-[1-(1,3-dioxoisoindolin-2-yl)oxycarbonylcyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate8 (1.8 g, 3.30 mmol, 87.06% yield, 88% purity) as sticky red. LC MS: ES+481.1.

Step 6: Synthesis of tert-butyl4-[4-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate:To a culture tube equipped with a stir bar were added tert-butyl4-[4-[1-(1,3-dioxoisoindolin-2-yl)oxycarbonylcyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate 8 (2.5 g, 5.20 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(3.96 g, 15.61 mmol), Lithium hydroxide, monohydrate (3.27 g, 78.04mmol, 2.17 mL), dichloromagnesium (743.04 mg, 7.80 mmol) and copper;(Z)-4-oxopent-2-en-2-olate (408.57 mg, 1.56 mmol). The tube wasevacuated and backfilled with argon for 3 times. Degassed Dioxane (14mL) and DMF (6.5 mL) in 1:2 ratio was added and the resulting mixturewas stirred under 1000 rpm at RT until dark brown colour was observed(typical reaction time <10 min). The reaction mixture was diluted withEtOAc and saturated solution of ammonium chloride, and the resultingmixture was shaken vigorously until getting a clear biphasic solution.The organic phase was collected and dried over anhydrous Na₂SO₄. It wasevaporated and purified by silica gel chromatography using 15%-20%EtOAc-Hexane as eluent to afford tert-butyl4-[4-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate9 (1.2 g, 2.73 mmol, 52.50% yield, 95% purity) as light yellow liquid.LC MS: ES+ 418.0.

Step 7: Synthesis of[1-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]cyclopropyl]-trifluoro-potassio-boron:To a stirred solution of tert-butyl4-[4-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate9 (1.4 g, 3.35 mmol) in Methanol (10 mL) was added potassium; fluoride;hydrofluoride (2.10 g, 26.84 mmol) and stirred the reaction mixture at80° C. for 16 hours. The reaction mixture was cooled to room temperatureand concentrated. Resulting residue was triturated with 50% ether inheptane (50 mL) for 10 min. The precipitate was collected by filtration,and rinsed with 100% ether (The filtrate contained pinacol). Theprecipitate was dissolved in hot acetonitrile (100 mL) and filtered toremove KHF₂. The filtrate was collected and lyophilized to afford[1-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]cyclopropyl]-trifluoro-potassio-boron10 (800 mg, 1.99 mmol, 59.43% yield, 99% purity) as floppy white solid.¹H NMR (400 MHz, DMSO-d6) δ 7.19 (s, 1H), 7.02 (s, 1H), 4.14 (m, 1H),4.00-3.97 (m, 2H), 2.85-2.82 (m, 2H), 1.91-1.88 (m, 2H), 1.70-1.63 (m,2H), 1.40 (s, 9H), 0.47 (s, 2H), 0.05 (s, 2H); LC MS: ES+ 339(difluoro).

Step 8: Synthesis of tert-butyl4-[4-[1-[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate:In a screw cap sealed tube fitted with a septum was added6-bromo-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 11 (1.48 g, 4.03mmol) and[1-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]cyclopropyl]-trifluoro-potassio-boron10 (800 mg, 2.01 mmol) intoluene (15.30 mL) and Water (1.70 mL) wasadded Cesium carbonate (1.97 g, 6.04 mmol). The resulting mixture wasdegassed by bubbling Argon for 10 minutes, cataCXium® A PalladacycleGen. 3 (73.32 mg, 100.68 umol) was added to the reaction mixture. Thereaction was then heated to 95° C. for 16 hours. Upon cooling to roomtemperature, the reaction solution was filtered through celite, elutingwith EtOAc, and concentrated to get crude mass which was purified byPrep TLC using 30% EtOAc-Hexane as eluent to afford tert-butyl4-[4-[1-[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate12 (300 mg, 513.22 umol, 25.49% yield, 99% purity) as yellow solid. LCMS: ES+ 579.6.

Step 9: Synthesis of6-[1-[1-(4-piperidyl)pyrazol-4-yl]cyclopropyl]-1H-benzo[cd]indol-2-one:To a stirred solution of tert-butyl4-[4-[1-[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate12 (300 mg, 518.40 umol) in TFA (4 mL) was addedtrifluoromethanesulfonic acid (778.02 mg, 5.18 mmol, 454.98 uL) at roomtemperature then reaction mixture was stirred at RT for over night. LCMSshowed product mass response then reaction mixture was concentratedunder reduced pressured to get6[1-[1-(4-piperidyl)pyrazol-4-yl]cyclopropyl]-1H-benzo[cd]indol-2-one 13(180 mg, 354.32 umol, 68.35% yield, 93% purity) which was used in nextstep as crude mass of TFA salt. LC MS: ES+ 359.3.

Step 10: Synthesis of tert-butyl4-[4-[1-(2-oxo-1H-benzo[cd]indol-6-yl)cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate:To a stirred solution of6-[1-[1-(4-piperidyl)pyrazol-4-yl]cyclopropyl]-1H-benzo[cd]indol-2-one;2,2,2-trifluoroaceticacid 13 (180 mg, 380.99 umol) in DCM (5 mL) was added Triethyl amine(115.66 mg, 1.14 mmol, 159.31 uL), followed by Di-tert-butyl dicarbonate(83.15 mg, 380.99 umol, 87.43 uL). It was stirred at room temperaturefor 16 hours. Reaction mixture was concentrated under reduced pressure,diluted with water, extracted with ethyl acetate, the organic layer waswashed with saturated sodium bicarbonate solution, brine, dried oversodium sulfate and concentrated under reduced pressure. Crude materialwas purified by combi-flash eluting at 50% ethyl acetate in hexane toafford tert-butyl4-[4-[1-(2-oxo-1H-benzo[cd]indol-6-yl)cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate14 (160 mg, 345.44 umol, 90.67% yield, 99% purity) as yellow solid. LCMS: ES+ 459.4.

Step 11: Synthesis of tert-butyl4-[4-[1-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate:To the stirred solution of tert-butyl4-[4-[1-(2-oxo-1H-benzo[cd]indol-6-yl)cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate14 (160 mg, 348.93 umol) in THF (5 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (133.70 mg, 3.49 mmol, 60%purity) at cold condition and the reaction mixture was stirred at roomtemperature for 10 minutes followed by the addition of3-bromopiperidine-2,6-dione 15 (334.99 mg, 1.74 mmol) portion wise. Itwas then stirred at room temperature for 10 minutes and heated at 70° C.for 30 minutes. The reaction mixture was diluted with ethyl acetate,washed with cold water and the organic fraction was separated. It wasthen dried over anhydrous sodium sulphate and evaporated under reducedpressure to obtain the crude which was washed with ether and pentane toafford tert-butyl4-[4-[1-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate16 (150 mg, 260.69 umol, 74.71% yield, 99% purity) as yellow solid. LCMS: ES+ 570.6.

Step 12: Synthesis of3-[2-oxo-6-[1-[1-(4-piperidyl)pyrazol-4-yl]cyclopropyl]benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of tert-butyl4-[4-[1-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]cyclopropyl]pyrazol-1-yl]piperidine-1-carboxylate16 (150 mg, 263.32 umol) in Dioxane (1 mL) and cooled the reactionmixture to 0° C. followed by drop wised addition of 4M HCl in Dioxane (4mL), stirred the reaction mixture for 3 hours at RT. Reaction mixturewas concentrated under reduced pressure and triturated with ether, driedto afford3-[2-oxo-6-[1-[1-(4-piperidyl)pyrazol-4-yl]cyclopropyl]benzo[cd]indol-1-yl]piperidine-2,6-dione17 (120 mg, 234.78 umol, 89.16% yield, 99% purity) as yellow solid. LCMS: ES+ 470.4.

Step 13: Synthesis of3-[6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]cyclopropyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of3-[6-[1-[1-(1-chloro-4-piperidyl)pyrazol-4-yl]cyclopropyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione17 (65 mg, 128.46 umol) in DMF (1 mL) was added1-methylcyclobutanecarboxylic acid 18 (14.66 mg, 128.46 umol, 13.09 uL)followed by HATU (73.27 mg, 192.69 umol) and the reaction mixture wascooled to 0° C. was added DIPEA (83.01 mg, 642.30 umol, 111.87 uL), thereaction mixture was allowed to stirred at room temperature forovernight. Reaction mixture was diluted with water and was extractedwith ethyl acetate, organic layer was washed with saturated sodiumbicarbonate solution(3×) followed by water and brine, dried over sodiumsulphate and concentrated under reduced pressure to get the crudeproduct. The crude product thus obtained was purified by Prep TLC using2% of MeOH in DCM as eluent to afford3-[6-[1-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]cyclopropyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 163 (55 mg, 92.37 umol, 71.91% yield, 95% purity) as lightyellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.35 (d, J=8.24Hz, 1H), 8.07 (d, J=6.96 Hz, 1H), 7.81 (t, J=7.62 Hz, 1H), 7.53 (d,J=7.32 Hz, 1H), 7.39 (s, 1H), 7.10-7.07 (m, 2H), 5.44 (dd, J=12.8, 5.16Hz, 1H), 4.35-4.25 (m, 1H), 4.22-4.19 (m, 1H), 3.57-3.56 (m, 1H),2.99-2.91 (m, 2H), 2.77-2.73 (m, 1H), 2.67-2.63 (m, 2H), 2.39-2.34 (m,2H), 2.10-2.07 (m, 1H), 1.93-1.86 (m, 3H), 1.78-1.75 (m, 1H), 1.64-1.58(m, 2H), 1.32 (br s, 5H), 1.23 (br s, 2H); LC MS: ES+ 566.5.

Step 14: Synthesis of3-[6-[1-[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]cyclopropyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To the stirred solution of3-[6-[1-[1-(1-chloro-4-piperidyl)pyrazol-4-yl]cyclopropyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione17 (40 mg, 79.05 umol) in THF (2 mL) was added Triethylamine (16.00 mg,158.10 umol, 22.04 uL) followed by the addition of1-methylcyclobutanecarbaldehyde 19 (7.76 mg, 79.05 umol, 7.68 uL),Dibutyltindichloride (28.82 mg, 94.86 umol, 21.19 uL) and Phenylsilane(8.55 mg, 79.05 umol, 9.74 uL). The reaction mixture was then stirred at90° C. for 16 hours. The reaction mixture was diluted with ethylacetate, washed with sodium bicarbonate solution, water and brinesolution. The organic fraction was separated. It was dried overanhydrous sodium sulphate, evaporated under reduced pressure to obtainthe crude compound which was purified by flash chromatography using 0-5%MeOH-DCM to afford3-[6-[1-[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]cyclopropyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 164 (20 mg, 35.88 umol, 45.39% yield, 98.97% purity) as yellowsolid. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.35 (d, J=8.32 Hz,1H), 8.06 (d, J=6.48 Hz, 1H), 7.80 (t, J=7.72 Hz, 1H), 7.53 (d, J=7.56Hz, 1H), 7.34 (s, 1H), 7.08-7.07 (m, 1H), 5.45-5.43 (m, 1H), 3.91-3.89(m, 1H), 2.96-2.92 (m, 1H), 2.80-2.59 (m, 3H), 2.20 (s, 2H), 2.08-2.07(m, 1H), 1.99-1.97 (m, 2H), 1.92-1.87 (m, 1H), 1.79-1.77 (m, 6H),1.58-1.56 (m, 2H), 1.31-1.29 (m, 2H), 1.24-1.23 (m, 2H), 1.11 (s, 3H);LC MS: ES+ 552.3.

Example 77. Synthesis of4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]-N-methyl-anilino]-1-piperidyl]-3-fluoro-benzonitrile(Compound 165)

Step 1: Synthesis of 6-[(4-nitrophenyl)methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of 1-(bromomethyl)-4-nitro-benzene (1) (10 g,46.29 mmol) intoluene (60 mL) and Ethanol (30 mL) was added6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(2) (20.49 g, 69.43 mmol) and Potassium phosphate tribasic anhydrous(29.48 g, 138.87 mmol). The resultant reaction mixture was degassed withArgon for 10 min then Pd2(dba)3 (4.24 g, 4.63 mmol) and Tri-o-Tolylphosphine (2.82 g, 9.26 mmol) were added and the reaction was heated at100° C. for 16 hr. After completion of the reaction (monitored by TLC)the reaction mixture was diluted with ethyl acetate and washed withwater and brine, dried over sodium sulphate and concentrated. The crudewas purified by column chromatography in 100-200 silica in 40-50% EtOAcin hexane to afford 6-[(4-nitrophenyl)methyl]-1H-benzo[cd]indol-2-one(3) (5 g, 28.40% yield) as brown solid. LC MS: ES+ 305.21.

Step 2: Synthesis of 6-[(4-aminophenyl)methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of6-[(4-nitrophenyl)methyl]-1H-benzo[cd]indol-2-one (3) (5 g, 16.43 mmol)in Methanol (50 mL) Argon gas was purged for 10 min then Pd-C (2.99 g,24.65 mmol) was added and the reaction was stirred under Hydrogenatmosphere (Balloon) for 16 hours at RT. The reaction mixture wasfiltered through celite and washed with 10% MeOH in DCM. The filtratethus obtained was concentrated under reduced pressure to afford6-[(4-aminophenyl)methyl]-1H-benzo[cd]indol-2-one (4) (3.5 g, 63.67%yield) as brown solid. LC MS: ES+ 275.15.

Step 3: Synthesis of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate:To a stirred solution of6-[(4-aminophenyl)methyl]-1H-benzo[cd]indol-2-one (4) (1.75 g, 6.38mmol) in THF (30 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate(5) (1.40 g, 7.02 mmol) followed by the addition of Dibutyltindichloride(2.33 g, 7.66 mmol, 1.71 mL) and Phenylsilane (690.33 mg, 6.38 mmol,786.25 uL). The reaction mixture was then stirred at 90° C. for 16 hoursin a sealed tube. The reaction mixture was diluted with ethyl acetate,washed with sodium bicarbonate solution, water and brine solution. Theorganic fraction was separated. It was dried over anhydrous sodiumsulphate, evaporated under reduced pressure to obtain the crude compoundwhich was purified by combiflash chromatography using 30-40% EtOAc inDCM to afford tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate(6) (1.3 g, 39.64% yield) as yellow solid. LC MS: ES+ 458.4.

Step 4: Synthesis of tert-butyl4-[N-methyl-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate:To a stirred solution of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate(6) (550 mg, 1.20 mmol) in Acetonitrile (7 mL) was added Formaldehyde,37% w/w aq. soln., (360.61 mg, 12.02 mmol, 1 mL) and Acetic acid (1.01g, 16.83 mmol, 962.42 uL) at 0° C. and the reaction mixture was stirredat that temperature for 1 hour. Then to it was added Sodiumcyanoborohydride (196.39 mg, 3.13 mmol) at that temperature and thereaction was slowly warmed to RT and continued for 16 hours. Aftercompletion of the reaction (monitored by TLC) the reaction mixture wasdiluted with ethyl acetate, washed with water and brine solution. Theorganic fraction was dried over anhydrous sodium sulphate and evaporatedunder reduced pressure to obtain the crude which was purified bycombiflash column (Gradient 15% EtOAc in DCM) to afford tert-butyl4-[N-methyl-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate(7) (350 mg, 55.57% yield) as greenish yellow solid. LC MS: ES+ 472.4.

Step 5: Synthesis of6-[[4-[methyl(4-piperidyl)amino]phenyl]methyl]-1H-benzo[cd]indol-2-one;hydrochloride salt: To a stirred solution of tert-butyl4-[N-methyl-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate(7) (350 mg, 742.17 umol) in Dioxane (5 mL) was added Dioxane-HCl(742.17 umol, 15 mL) and the reaction was stirred at RT for 3 hours.After completion of the reaction (monitored by TLC) The reaction mixturewas concentrated to dryness and triturated with ether to afford6-[[4-[methyl(4-piperidyl)amino]phenyl]methyl]-1H-benzo[cd]indol-2-one;hydrochloride (8) (300 mg, 79.27% yield) as yellow solid. LC MS: ES+372.2.

Step 6: Synthesis of3-fluoro-4-[4-[N-methyl-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]-1-piperidyl]benzonitrile:To a stirred solution of6-[[4-[methyl(4-piperidyl)amino]phenyl]methyl]-1H-benzo[cd]indol-2-one;hydrochloride (8) (300 mg, 735.41 umol) in NMP (4 mL) was added DIPEA(475.22 mg, 3.68 mmol, 640.46 uL) followed by 3,4-difluorobenzonitrile(9) (102.30 mg, 735.41 umol) and the resulting reaction mixture wasstirred at 90° C. for 16 hours. After completion (monitored by TLC) thereaction mixture was diluted with ethyl acetate and washed with waterand brine, dried over sodium sulphate and concentrated. The crude waspurified by combiflash column in 30% EtOAc in DCM to afford3-fluoro-4-[4-[N-methyl-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]-1-piperidyl]benzonitrile(10) (100 mg, 20.51% yield) as yellow gum. LC MS: ES+ 491.4.

Step 7: Synthesis of4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]-N-methyl-anilino]-1-piperidyl]-3-fluoro-benzonitrile:To a stirred solution of3-fluoro-4-[4-[N-methyl-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]-1-piperidyl]benzonitrile(10) (100 mg, 203.84 umol) in THF (5 mL) was added Sodium hydride (inoil dispersion) 60% dispersion in mineral oil (46.86 mg, 2.04 mmol) at0° C. and stirred for 5 min. Then 3-bromopiperidine-2,6-dione (11)(195.70 mg, 1.02 mmol) was added under cooling condition and thereaction mixture was stirred at 70° C. for 30 min. After completion(monitored by TLC) the reaction mixture was quenched in ice andextracted with ethyl acetate. The organic part was further washed withwater and brine, dried over sodium sulfate and concentrated. The crudewas purified by Prep TLC Plate in 20% EtOAc in DCM to afford4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]-N-methyl-anilino]-1-piperidyl]-3-fluoro-benzonitrileCompound 165 (35 mg, 28.18% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.33 (d, J=8.24 Hz, 1H), 8.06 (d, J=6.96 Hz,1H), 7.80 (t, J=7.58 Hz, 1H), 7.68-7.65 (m, 1H), 7.54 (d, J=8.44 Hz,1H), 7.36 (d, J=7.24 Hz, 1H), 7.15-7.07 (m, 4H), 6.75 (d, J=8.52 Hz,2H), 5.43 (dd, J=12.24, 5.08 Hz, 1H), 4.26 (s, 2H), 3.78-3.76 (m, 1H),3.63-3.60 (m, 2H), 2.96-2.90 (m, 3H), 2.77-2.73 (m, 1H), 2.66-2.62 (m,4H), 2.08-2.07 (m, 1H), 1.80-1.74 (m, 2H), 1.68-1.65 (m, 2H); LC MS: ES+602.2.

Example 78. Synthesis of4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]anilino]-1-piperidyl]-3-fluoro-benzonitrile(Compound 166)

Step 1: Synthesis of 6-[(4-nitrophenyl)methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of 1-(bromomethyl)-4-nitro-benzene (1) (10 g,46.29 mmol) intoluene (60 mL) and Ethanol (30 mL) was added6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(2) (20.49 g, 69.43 mmol) and Potassium phosphate tribasic anhydrous(29.48 g, 138.87 mmol). The resultant reaction mixture was degassed withArgon for 10 min then Pd2(dba)3 (4.24 g, 4.63 mmol) and Tri-o-Tolylphosphine (2.82 g, 9.26 mmol) were added and the reaction was heated at100° C. for 16 hours. After completion of the reaction (monitored byTLC) the reaction mixture was diluted with ethyl acetate and washed withwater and brine, dried over sodium sulphate and concentrated. The crudewas purified by column chromatography (silica, gradient: 40-50% EtOAc inHexane) to afford 6-[(4-nitrophenyl)methyl]-1H-benzo[cd]indol-2-one (3)(5 g, 28.40% yield) as brown solid. LC MS: ES+ 305.21.

Step 2: Synthesis of 6-[(4-aminophenyl)methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of6-[(4-nitrophenyl)methyl]-1H-benzo[cd]indol-2-one (3) (5 g, 16.43 mmol)in Methanol (50 mL) Argon gas was purged for 10 min then Pd-C (2.99 g,24.65 mmol) was added and the reaction was stirred under Hydrogenatmosphere (Balloon) for 16 hours at RT. The reaction mixture wasfiltered through celite and washed with 10% MeOH in DCM. The filtratethus obtained was concentrated under reduced pressure to afford6-[(4-aminophenyl)methyl]-1H-benzo[cd]indol-2-one (4) (3.5 g, 63.67%yield) as brown solid. LC MS: ES+ 275.15.

Step 3: Synthesis of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate:To a stirred solution of6-[(4-aminophenyl)methyl]-1H-benzo[cd]indol-2-one (4) (1.75 g, 6.38mmol) in THF (30 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate(5) (1.40 g, 7.02 mmol) followed by the addition of Dibutyltindichloride(2.33 g, 7.66 mmol, 1.71 mL) and Phenylsilane (690.33 mg, 6.38 mmol,786.25 uL). The reaction mixture was then stirred at 90° C. for 16 hoursin a sealed tube. After completion of the reaction (monitored by TLC)the reaction mixture was diluted with ethyl acetate, washed with sodiumbicarbonate solution, water and brine solution. The organic fraction wasseparated. It was dried over anhydrous sodium sulphate, evaporated underreduced pressure to obtain the crude compound which was purified bycombiflash chromatography using 30-40% EtOAc in DCM to afford tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate(6) (1.3 g, 39.64% yield) as yellow solid. LC MS: ES+ 458.4.

Step 4: Synthesis of6-[[4-(4-piperidylamino)phenyl]methyl]-1H-benzo[cd]indol-2-one;hydrochloride salt: To a stirred solution of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]piperidine-1-carboxylate(6) (500 mg, 1.09 mmol) in Dioxane HCl (5 mL) was added Dioxan-HCl (15mL) and the reaction mixture was stirred at RT for 3 hours. Aftercompletion of the reaction (monitored by TLC) The reaction mixture wasconcentrated to dryness and triturated with ether to afford6-[[4-(4-piperidylamino)phenyl]methyl]-1H-benzo[cd]indol-2-one;hydrochloride (7) (350 mg, 81.31% yield) as yellow solid. LC MS: ES+357.1.

Step 5: Synthesis of3-fluoro-4-[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]-1-piperidyl]benzonitrile:To a stirred solution of6-[[4-(4-piperidylamino)phenyl]methyl]-1H-benzo[cd]indol-2-one;hydrochloride (7) (350 mg, 888.53 umol) in DMF (4 mL) was added DIPEA(574.18 mg, 4.44 mmol, 773.83 uL) followed by 3,4-difluorobenzonitrile(8) (123.60 mg, 888.53 umol) and the resulting reaction mixture wasstirred at 90° C. for 16 hours. After completion of the reaction(monitored by TLC) the reaction mixture was diluted with ethyl acetateand washed with water and brine, dried over sodium sulphate andconcentrated. The crude was purified by combiflash column in 30% EtOAcin DCM to afford3-fluoro-4-[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]-1-piperidyl]benzonitrile(9) (200 mg, 33.06% yield) as yellow gum. LC MS: ES+ 477.3.

Step 6: Synthesis of4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]anilino]-1-piperidyl]-3-fluoro-benzonitrile:To a stirred solution of3-fluoro-4-[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]anilino]-1-piperidyl]benzonitrile(9) (70 mg, 146.89 umol) in THF (5 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (56.28 mg, 1.47 mmol, 60%purity) at 0° C. and stirred for 5 min. Then 3-bromopiperidine-2,6-dione(10) (141.02 mg, 734.46 umol) was added under cooling condition and thereaction was stirred at 70° C. for 30 min. After completion of thereaction (monitored by TLC) the reaction mixture was quenched in ice andextracted with ethyl acetate. The organic part was further washed withwater and brine, dried over sodium sulfate and concentrated. The crudewas purified by Prep TCL Plate in 20% EtOAc in DCM to afford4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]anilino]-1-piperidyl]-3-fluoro-benzonitrileCompound 166 (30 mg, 34.21% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.32 (d, J=8.44 Hz, 1H), 8.06 (d, J=6.88 Hz,1H), 7.80 (t, J=7.76 Hz, 1H), 7.67-7.64 (m, 1H), 7.54 (d, J=8.36 Hz,1H), 7.34 (d, J=7.0 Hz, 1H), 7.14-7.06 (m, 2H), 6.99 (d, J=8.12 Hz, 2H),6.52 (d, J=Hz, 2H), 5.45-5.42 (m, 1H), 5.35 (d, J=8.52 Hz, 1H), 4.21 (s,2H), 3.54-3.51 (m, 2H), 2.98-2.92 (m, 4H), 2.76-2.73 (m, 1H), 2.66-2.63(m, 1H), 2.09-2.07 (m, 1H), 1.98-1.94 (m, 2H), 1.46-1.43 (m, 2H)LC MS:ES+ 588.2.

Example 79. Synthesis of3-[6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 167)

Step 1: Synthesis of tert-butyl4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperazine-1-carboxylate:To a stirred solution of tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate(1) (1.4 g, 3.61 mmol) and6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (2)(2.44 g, 7.21 mmol) intoluene (30 mL) and Ethanol (10 mL) was addedPotassium phosphate tribasic anhydrous (2.30 g, 10.82 mmol) and thereaction mass was degassed with nitrogen for 10 minutes. ThenTri-o-Tolyl phosphine (219.47 mg, 721.08 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (330.15 mg, 360.54umol) were added and it was heated at 90° C. for 16 hours. Aftercompletion (monitored by TLC) the reaction mixture was passed throughcelite bed and washed with EtOAc. The filtrate was then washed withwater and brine, dried over sodium sulphate and concentrated. The crudethus obtained was purified by combiflash column in (gradient: 0-30%EtOAc in DCM) to afford the desired compound tert-butyl4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperazine-1-carboxylate(3) (1.4 g, 41.33% yield) as brown gum. LC MS: ES+ 564.2.

Step 2: Synthesis of6-[(4-piperazin-1-ylphenyl)methyl]-1H-benzo[cd]indol-2-one: To a stirredsolution of tert-butyl4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperazine-1-carboxylate(3) (2.2 g, 3.90 mmol) in TFA (10 mL) was added trifluoromethanesulfonicacid (5.86 g, 39.03 mmol, 3.43 mL) under cooling condition. Then thereaction mixture was stirred at room temperature for 16 hr. Aftercompletion (monitored by TLC and LCMS) the reaction mass was quenchedwith saturated bicarbonate solution and extracted with ethyl acetate(twice). The combined organic part was dried over Sodium sulphate andconcentrated under reduced pressure to afford6-[(4-piperazin-1-ylphenyl)methyl]-1H-benzo[cd]indol-2-one (4) (1.3 g,67.89% yield) as brown gum. LC MS: ES+ 344.1.

Step 3: Synthesis of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]piperazine-1-carboxylate:To a stirred solution of6-[(4-piperazin-1-ylphenyl)methyl]-1H-benzo[cd]indol-2-one (4) (1.3 g,3.79 mmol) in DCM (20 mL) was added Triethyl Amine (1.15 g, 11.36 mmol,1.58 mL) under cooling condition. Then Di-tert-butyl dicarbonate (991.41mg, 4.54 mmol, 1.04 mL) was added and the resultant reaction mixture wasstirred at room temperature for 16 h. After completion (monitored byTLC) the reaction mixture was diluted with DCM and washed with water andbrine, dried over Na₂SO₄ and concentrated under reduced pressure. Thecrude thus obtained was purified by combi-flash column (gradient: 0-30%EtOAc in DCM) to afford pure compound tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]piperazine-1-carboxylate(5) (730 mg, 42.10% yield) as yellow solid. LC MS: ES+ 444.5.

Step 4: Synthesis of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperazine-1-carboxylate:To a stirred solution of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]piperazine-1-carboxylate(5) (700 mg, 1.58 mmol) in dry THF (15 mL) was added Sodium hydride 60%dispersion in mineral oil (604.72 mg, 15.78 mmol) at 0° C. and stirredfor 15 minutes followed by the addition of 3-bromopiperidine-2,6-dione(6) (1.97 g, 10.26 mmol). After completion (monitored by TLC) thereaction mixture was quenched in ice and extracted with ethyl acetate.The organic part was further washed with water and brine, dried oversodium sulfate and concentrated. The crude was purified by Combiflashcolumn (30% EtOAc in DCM) to afford tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperazine-1-carboxylate(7) (700 mg, 70.37% yield) as yellow solid. LC MS: ES+ 555.3.

Step 5: Synthesis of3-[2-oxo-6-[(4-piperazin-1-ylphenyl)methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione;Hydrocloride salt: To a stirred solution of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperazine-1-carboxylate(7) (700 mg, 1.26 mmol) in Dioxane (3 mL) was added Dioxane-HCl (15 mL)at 0° C. and the resulting reaction mixture was stirred at roomtemperature for 3 hours. After completion (monitored by TLC) thereaction mixture was concentrated under reduced pressure. The crude wastriturated with ether to afford the desired compound3-[2-oxo-6-[(4-piperazin-1-ylphenyl)methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione;Hydrocloride salt (8) (550 mg, 86.19% yield) as yellow solid. LC MS: ES+455.5.

Step 6: Synthesis of3-[6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of 1-methylcyclobutanecarboxylic acid (9) (50.23mg, 440.03 umol) in DMF (5 mL) were added DIPEA (284.34 mg, 2.20 mmol,383.21 uL) and HATU (200.77 mg, 528.03 umol). The resultant reactionmixture was then stirred at RT for 15 minutes followed by the additionof3-[2-oxo-6-[(4-piperazin-1-ylphenyl)methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione(8) (200 mg, 440.03 umol) and stirred at RT for 16 hours. Aftercompletion (monitored by LCMS), the reaction mixture was diluted withEthyl acetate and washed with cold water, brine, dried over sodiumsulphate and concentrated under reduced pressure. The crude thusobtained was purified by Prep TLC Plate (50% ethyl acetate in DCM) toafford the desired compound3-[6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 167 (84.0 mg, 34.04% yield) as light yellow solid. ¹H NMR (400MHz, DMSO-d6) δ 11.09 (s, 1H), 8.28 (d, J=8.28 Hz, 1H), 8.03 (d, J=6.92Hz, 1H), 7.76 (t, J=7.62 Hz, 1H), 7.34 (d, J=7.32 Hz, 1H), 7.13-7.05 (m,3H), 6.82 (d, J=8.44 Hz, 2H), 5.40 (dd, J=12.88, 5.44 Hz, 1H), 4.26 (s,2H), 3.52-3.50 (m, 2H), 3.30-3.29 (m, 2H), 2.98 (br s, 4H), 2.92-2.86(m, 1H), 2.75-2.70 (m, 1H), 2.64-2.60 (m, 1H), 2.47-2.33 (m, 2H),2.07-2.04 (m, 1H), 1.90-1.85 (m, 1H), 1.78-1.73 (m, 2H), 1.59-1.56 (m,1H), 1.31 (s, 3H); LC MS: ES+ 551.2.

Example 80. Synthesis of3-[6-[[4-[4-[(1-methylcyclobutyl)methyl]piperazin-1-yl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 168)

Step-1: Synthesis of3-[6-[[4-[4-[(1-methylcyclobutyl)methyl]piperazin-1-yl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of3-[6-[[4-(4-chloropiperazin-1-yl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(1) (200.0 mg, 407.35 umol) in THF (6 mL) was added Triethylamine (82.44mg, 814.70 umol, 113.55 uL) followed by the addition of1-methylcyclobutanecarbaldehyde (2) (39.98 mg, 407.35 umol, 39.19 uL),Dibutyltindichloride (148.53 mg, 488.82 umol, 109.21 uL) andPhenylsilane (44.08 mg, 407.35 umol, 50.20 uL). The reaction mixture wasthen stirred at 90° C. for 16 hours. After completion (monitored by TLCand LCMS) the reaction mass was quenched with saturated bicarbonatesolution and extracted with ethyl acetate. The organic layer wasseparated and washed with brine, dried over sodium sulphate andconcentrated under reduced pressure. The crude this obtained waspurified by combiflash chromatography (gradient: 0-1% MeoH in DCM) toafford the desired compound3-[6-[[4-[4-[(1-methylcyclobutyl)methyl]piperazin-1-yl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 168 (70 mg, 30.42% yield) as light yellow solid. ¹H NMR (400MHz, DMSO-d6) δ 11.11 (s, 1H), 8.31 (d, J=8.24 Hz, 1H), 8.06 (d, J=6.96Hz, 1H), 7.79 (t, J=7.62 Hz, 1H), 7.36 (d, J=7.32 Hz, 1H), 7.11-7.07 (m,3H), 6.80 (d, J=8.44 Hz, 2H), 5.43 (dd, J=12.76, 5.04 Hz, 1H), 4.27 (s,2H), 3.00-2.99 (m, 4H), 2.94-2.90 (m, 1H), 2.77-2.72 (m, 1H), 2.66-2.62(m, 1H), 2.40 (br s, 4H), 2.24 (s, 2H), 2.10-2.07 (m, 1H), 1.94-1.90 (m,1H), 1.86-1.82 (m, 2H), 1.79-1.71 (m, 1H), 1.62-1.58 (m, 2H), 1.15 (s,3H); LC MS: ES+ 536.9.

Example 81. Synthesis of3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 169)

Step 1: Synthesis of tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate:To a stirred solution of tert-butyl4-(4-bromophenyl)piperidine-1-carboxylate (1) (2 g, 5.88 mmol) in1,4-dioxane (40 mL) was added Bis(pinacolato)Diboron (2.24 g, 8.82 mmol)and potassium; acetate (1.73 g, 17.63 mmol). Then Nitrogen gas waspurged for 15 minutes. Followed by the addition ofcyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(480.02 mg, 587.80 umol). The resultant reaction mixture was thenstirred at 90° C. for 16 hours. After completion (monitored by TLC andLCMS) the reaction mixture was filtered through celite pad and washedwith ethyl acetate. The filtrate was then washed with water and brine,dried over sodium sulphate and concentrated to afford tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate(2) (2.2 g, 96.63% yield). LC MS: ES+ 388.5.

Step 2: Synthesis of tert-butyl4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate:To a stirred solution of4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate(2) (2.06 g, 5.33 mmol) and6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (3)(1.5 g, 4.44 mmol) intoluene (32 mL) and Ethanol (16 mL) was addedPotassium phosphate tribasic anhydrous (2.83 g, 13.32 mmol) and thereaction mass was degassed with nitrogen for 10 minutes. ThenTri-o-Tolyl phosphine (270.31 mg, 888.10 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (406.63 mg, 444.05umol) were added and it was heated at 90° C. for 16 h. After completion(monitored by TLC) the reaction mixture was passed through celite bedand washed with EtOAc. The filtrate was then washed with water andbrine, dried over sodium sulphate and concentrated. The crude thusobtained was purified by combiflash column in (gradient: 0-20% EtOAc inHexane) to afford the desired compound tert-butyl4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate(4) (1.5 g, 57.03% yield) as off white solid. LC MS: ES+ 563.06.

Step 3: Synthesis of6-[[4-(4-piperidyl)phenyl]methyl]-1H-benzo[cd]indol-2-one: To a stirredsolution of tert-butyl4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate(4) (1.8 g, 3.20 mmol) in TFA (5 mL) was added trifluoromethanesulfonicacid (4.80 g, 31.99 mmol, 2.81 mL) under cooling condition. Then thereaction mixture was stirred at room temperature for 16 hours. Aftercompletion (monitored by TLC and LCMS) the reaction mass was quenchedwith saturated bicarbonate solution and extracted with ethyl acetate(twice). The combined organic part was dried over Sodium sulphate andconcentrated under reduced pressure to afford6-[[4-(4-piperidyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (5) (800 mg,65.73% yield) as brown gum. LC MS: ES+ 343.1.

Step 4: Synthesis oftert-butyl-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]piperidine-1-carboxylate:To a stirred solution of6-[[4-(4-piperidyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (5) (800 mg,2.34 mmol) in DCM (20 mL) was added Triethyl Amine (709.21 mg, 7.01mmol, 976.87 uL) under cooling condition. Then Di-tert-butyl dicarbonate(611.85 mg, 2.80 mmol, 643.37 uL) was added and the resultant reactionmixture was stirred at room temperature for 16 h. After completion(monitored by TLC) the reaction mixture was diluted with DCM and washedwith water and brine, dried over Na₂SO₄ and concentrated under reducedpressure. The crude thus obtained was purified by combi-flash column(gradient: 0-20% EtOAc in DCM) to afford pure compound tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]piperidine-1-carboxylate(6) (400 mg, 36.75% yield) as yellow solid. LC MS: ES+ 387.6, (M-56Present).

Step 5: Synthesis of4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate:To a stirred solution of tert-butyl1-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]piperidine-4-carboxylate(6) (400 mg, 903.86 umol) in dry THF (10 mL) was added Sodium hydride60% dispersion in mineral oil (519.49 mg, 13.56 mmol) at 0° C. andstirred for 15 minutes followed by the addition of3-bromopiperidine-2,6-dione (7) (867.75 mg, 4.52 mmol). After completion(monitored by TLC) the reaction mixture was quenched in ice andextracted with ethyl acetate. The organic part was further washed withwater and brine, dried over sodium sulfate and concentrated. The crudewas purified by Combiflash column (30% EtOAC in DCM) to afford4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate(8) (300 mg, 53.95% yield) as yellow solid. LC MS: ES+ 454.5, (M+H)-100present).

Step 6: Synthesis of3-[2-oxo-6-[[4-(4-piperidyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione;Hydrochloride salt: To a stirred solution of tert-butyl tert-butyl1-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperidine-4-carboxylate(8) (300 mg, 541.86 umol) in Dioxane (3 mL) was added Dioxane-HCl (10mL) at 0° C. and the resulting reaction mixture was stirred at roomtemperature for 3 hours. After completion (monitored by TLC) thereaction mixture was concentrated under reduced pressure. The crude wastriturated with Ether-Pentane to afford the desired compound3-[2-oxo-6-[[4-(4-piperidyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione(9) (260 mg, 97.03% yield) as yellow solid. LC MS: ES+ 454.38.

Step 7: Synthesis of3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To the stirred solution of3-[2-oxo-6-[[4-(4-piperidyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione(9) (110 mg, 242.54 umol) and 1-methylcyclobutanecarboxylic acid (10)(27.68 mg, 242.54 umol) in DMF (50 mL) was added DIPEA (156.73 mg, 1.21mmol, 211.23 uL) and stirred for 15 minutes followed by the addition ofHATU (110.67 mg, 291.05 umol) and was allowed to stir for 16 hours atRT. After completion (monitored by LCMS), the reaction mixture wasdiluted with Ethyl acetate and washed with cold water, brine, dried oversodium sulphate and concentrated under reduced pressure. The crude thusobtained was purified by column chromatography (silica, gradient: 0-2%MeOH in DCM) to afford3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 169 (72.0 mg, 53.75% yield) as light yellow solid. ¹H NMR (400MHz, DMSO-d6) δ 11.11 (s, 1H), 8.33 (d, J=8.2 Hz, 1H), 8.06 (d, J=6.92Hz, 1H), 7.80 (t, J=7.58 Hz, 1H), 7.40 (d, J=7.2 Hz, 1H), 7.22-7.19 (m,2H), 7.15-7.07 (m, 3H), 5.43 (dd, J=12.52, 5.0 Hz, 1H), 4.47-4.45 (m,1H), 4.34 (s, 2H), 3.58-3.57 (m, 1H), 2.99-2.88 (m, 2H), 2.80-2.56 (m,4H), 2.41-2.39 (m, 2H), 2.10-2.07 (m, 1H), 1.93-1.84 (m, 1H), 1.77-1.70(m, 4H), 1.63-1.61 (m, 1H), 1.58-1.40 (m, 2H), 1.33 (s, 3H); LC MS: ES+550.3.

Example 82. Synthesis of3-[6-[[4-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 170)

Step 1: Synthesis of3-[6-[[4-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of3-[6-[[4-(1-chloro-4-piperidyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(1) (200 mg, 408.17 umol) in THF (6 mL) was added Triethylamine (82.44mg, 814.70 umol, 113.55 uL) followed by the addition of1-methylcyclobutanecarbaldehyde (2) (40.06 mg, 408.17 umol, 39.27 uL),Dibutyltindichloride (148.83 mg, 489.80 umol, 109.43 uL) andPhenylsilane (44.17 mg, 408.17 umol, 50.31 uL). The reaction mixture wasthen stirred at 90° C. for 48 hours in a sealed tube. After completion(monitored by TLC and LCMS) the reaction mass was quenched withsaturated bicarbonate solution and extracted with ethyl acetate. Theorganic layer was separated and washed with brine, dried over sodiumsulphate and concentrated under reduced pressure. The crude thisobtained was purified by combiflash chromatography (gradient: 0-1% MeoHin DCM) to afford the desired compound3-[6-[[4-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 170 (50 mg, 22.87% yield) as light yellow solid. ¹H NMR (400MHz, DMSO-d6) δ 11.11 (s, 1H), 8.33 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.96Hz, 1H), 7.80 (t, J=7.62 Hz, 1H), 7.42-7.40 (m, 1H), 7.25-7.18 (m, 2H),7.13-7.09 (m, 3H), 5.46-5.43 (m, 1H), 4.34 (s, 2H), 3.33-3.31 (m, 1H),3.13-3.10 (m, 1H), 2.96-2.92 (m, 1H), 2.78-2.74 (m, 2H), 2.70-2.62 (m,1H), 2.33-2.31 (m, 1H), 2.21 (s, 1H), 2.10-2.07 (m, 1H), 1.99-1.72 (m,6H), 1.62-1.60 (m, 4H), 1.31-1.30 (m, 1H), 1.14 (s, 2H); LC MS: ES+536.3.

Example 83. Synthesis of4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenoxy]-1-piperidyl]-3-fluoro-benzonitrile(Compound 171)

Step 1: Synthesis of tert-butyl4-(4-methoxycarbonylphenoxy)piperidine-1-carboxylate: To a stirredsolution of Triphenylphosphine (3.91 g, 14.91 mmol) in THF (20 mL) wasadded Diisopropyl azodicarboxylate (3.01 g, 14.91 mmol, 2.93 mL) at 0°C. and it was stirred at room temperature for 15 minutes when thesolution became turbid, to it was added methyl 4-hydroxybenzoate (1) (2g, 13.15 mmol) followed by the addition of tert-butyl4-hydroxypiperidine-1-carboxylate (2) (2 g, 9.94 mmol) and the reactionwas continued at room temperature for 16 hours. After completion of thereaction (monitored by TLC) the reaction mixture was evaporated underreduced pressure and purified by column chromatography (Silica; gradient10-15% EtOAc in Hexane) to afford tert-butyl4-(4-methoxycarbonylphenoxy)piperidine-1-carboxylate (3) (1.8 g, 53.25%yield) as a white solid. LC MS: ES+ (M−100) 236.2.

Step 2: Synthesis of tert-butyl4-[4-(hydroxymethyl)phenoxy]piperidine-1-carboxylate: To a stirredsolution of tert-butyl4-(4-methoxycarbonylphenoxy)piperidine-1-carboxylate (3) (1.8 g, 5.37mmol) in THF (20 mL) was added Lithium aluminium hydride (728.22 mg,21.47 mmol) (portion wise) under cooling condition and the reaction wasstirred at RT for 16 h. After completion of the reaction (monitored byTLC) the reaction mixture was diluted with THF and cooled to 0° C. andto it was added Water (0.8 mL) followed by 15% aqueous NaOH (0.8 mL) andWater (2.4 mL) and then the reaction mixture was warmed to RT andstirred for 15 min. Then it was filtered off and the filtrate was driedunder reduced pressure. The crude was again diluted with ethyl acetateand washed with water and brine, dried over sodium sulfate andconcentrated to afford tert-butyl4-[4-(hydroxymethyl)phenoxy]piperidine-1-carboxylate (4) (1.2 g, 63.29%yield) as a white solid. LC MS: ES+ (M−100) 208.

Step 3: Synthesis of tert-butyl4-[4-(chloromethyl)phenoxy]piperidine-1-carboxylate: To a stirredsolution of tert-butyl4-[4-(hydroxymethyl)phenoxy]piperidine-1-carboxylate (4) (800 mg, 2.60mmol) in DCM (15 mL) was added Triethylamine (1.32 g, 13.01 mmol, 1.81mL) under cooling condition and the reaction was stirred for 5 min. ThenMesyl Chloride (1.19 g, 10.41 mmol, 805.76 uL) was added and thereaction was allowed to warm to RT and stirred for 16 hours. Aftercompletion of the reaction (monitored by TLC) the reaction mixture wasdiluted with DCM and washed with sat sodium bicarbonate and brine, driedover sodium sulphate and concentrated to afford tert-butyl4-[4-(chloromethyl)phenoxy]piperidine-1-carboxylate (5) (800 mg, 75.47%yield) as yellow sticky gum.

Step 4: Synthesis of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenoxy]piperidine-1-carboxylate:To a stirred solution of tert-butyl4-[4-(chloromethyl)phenoxy]piperidine-1-carboxylate (5) (800 mg, 2.46mmol) intoluene (12 mL) and Ethanol (6 mL) was added6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(6) (1.09 g, 3.68 mmol) and Potassium phosphate tribasic anhydrous (1.56g, 7.37 mmol). The resultant reaction mixture was degassed with Argonfor 10 min then Pd2(dba)3 (224.68 mg, 245.53 umol) and Tri-o-Tolylphosphine (149.46 mg, 491.05 umol) were added and the reaction washeated at 100° C. for 16 hr. After completion (monitored by TLC), thereaction mixture was diluted with ethyl acetate and washed with waterand brine, dried over sodium sulphate and concentrated. The crude thusobtained was purified by combiflash column (Gradient 20-30% EtOAc inDCM) to afford tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenoxy]piperidine-1-carboxylate(7) (400 mg, 31.98% yield) as yellow solid. LC MS: ES+ 459.5.

Step 5: Synthesis of6-[[4-(4-piperidyloxy)phenyl]methyl]-1H-benzo[cd]indol-2-one;hydrochloride: Dioxane-HCl (5 mL) was added to tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenoxy]piperidine-1-carboxylate(7) (400 mg, 872.32 umol) and the resultant reaction mixture was stirredat RT for 2 hours. After completion of the reaction (monitored by TLC),the reaction mixture was evaporated to dryness and triturated with etherto afford 6-[[4-(4-piperidyloxy)phenyl]methyl]-1H-benzo[cd]indol-2-one;hydrochloride (8) (340 mg, 72.29% yield) as yellow solid. LC MS: ES+359.3.

Step 6: Synthesis of3-fluoro-4-[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenoxy]-1-piperidyl]benzonitrile:To a stirred solution of6-[[4-(4-piperidyloxy)phenyl]methyl]-1H-benzo[cd]indol-2-one;hydrochloride (8) (340 mg, 860.99 umol) in NMP (5 mL) was added DIPEA(556.39 mg, 4.30 mmol, 749.85 uL) followed by 3,4-difluorobenzonitrile(9) (119.77 mg, 860.99 umol) and the resulting reaction mixture wasstirred at 90° C. for 16 hours. After completion of the reaction(monitored by TLC), the reaction mixture was diluted with ethyl acetateand washed with water and brine, dried over sodium sulphate andconcentrated. The crude was purified by combiflash column (gradient0-30% EtOAc in DCM) to afford3-fluoro-4-[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenoxy]-1-piperidyl]benzonitrile(10) (120 mg, 27.14% yield) as yellow gum. LC MS: ES+ 478.3.

Step 7: Synthesis of4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenoxy]-1-piperidyl]-3-fluoro-benzonitrile:To a stirred solution of3-fluoro-4-[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenoxy]-1-piperidyl]benzonitrile(10) (120 mg, 251.29 umol) in THF (5 mL) was added Sodium hydride 60%dispersion in mineral oil (57.77 mg, 2.51 mmol) at 0° C. and stirred for5 min. Then 3-bromopiperidine-2,6-dione (11) (241.26 mg, 1.26 mmol) wasadded under cooling condition and the reaction was stirred at 70° C. for30 min. After completion of the reaction (monitored by TLC) the reactionmixture was quenched in ice and extracted with ethyl acetate. Theorganic part was further washed with water and brine, dried over sodiumsulphate and concentrated. The crude was purified by Prep TCL Plate in20% EtOAc in DCM to afford4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenoxy]-1-piperidyl]-3-fluoro-benzonitrileCompound 171 (85 mg, 55.19% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.33 (d, J=8.24 Hz, 1H), 8.07 (d, J=6.72 Hz,1H), 7.81 (t, J=7.62 Hz, 1H), 7.69-7.65 (m, 1H), 7.54 (d, J=7.2 Hz, 1H),7.39 (d, J=7.28 Hz, 1H), 7.21-7.08 (m, 4H), 6.89 (d, J=8.44 Hz, 1H),5.45-5.41 (m, 1H), 4.52-4.51 (m, 1H), 4.32 (s, 2H), 3.41-3.35 (m, 2H),3.11-3.07 (m, 2H), 2.96-2.90 (m, 1H), 2.77-2.73 (m, 1H), 2.66-2.62 (m,1H), 2.09-2.07 (m, 1H), 2.01-2.00 (m, 2H), 1.73-1.72 (m, 2H) LC MS: ES+589.3.

Example 84. Synthesis of4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6yl]methyl]phenyl]methyl]-3-oxo-piperazin-1-yl]-3-fluoro-benzonitrile(Compound 172)

Step 1: Synthesis of tert-butyl4-[[4-(chloromethyl)phenyl]methyl]-3-oxo-piperazine-1-carboxylate: To astirred solution of tert-butyl 3-oxopiperazine-1-carboxylate (1) (2 g,9.99 mmol) in DMF (20 mL) Sodium hydride 60% dispersion in mineral oil(275.56 mg, 11.99 mmol) was added under cooling condition and thereaction was stirred for 20 min. Then 1,4-bis(chloromethyl)benzene (2)(1.75 g, 9.99 mmol, 1.23 mL) was added and the reaction was allowed tostir at RT for 16 h. The reaction mixture was quenched with ice andextracted with ethyl acetate. The organic part was dried over sodiumsulfate and concentrated. The crude was purified by columnchromatography in (100-200 silica; gradient 20-30% EtOAc in hexane) toafford tert-butyl4-[[4-(chloromethyl)phenyl]methyl]-3-oxo-piperazine-1-carboxylate (3)(1.5 g, 39.89% yield). LC MS: ES+ 339.0.

Step 2: Synthesis of3-oxo-4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazine-1-carboxylate:To a stirred solution of tert-butyl4-[[4-(chloromethyl)phenyl]methyl]-3-oxo-piperazine-1-carboxylate (3) (1g, 2.95 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(4) (1.05 g, 3.54 mmol) in ethanol (5 mL) and Toluene (10 mL) was addedPotassium phosphate tribasic anhydrous (1.88 g, 8.85 mmol) and thereaction mass was purged with Nitrogen for 15 min, then Tri-o-Tolylphosphine (179.66 mg, 590.27 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (270.26 mg, 295.13umol) were added and the reaction was heated at 90° C. for 16 hr. Aftercompletion (monitored by TLC) the reaction mixture was passed throughcelite bed and washed with EtOAc. The filtrate was then washed withwater and brine, dried over sodium sulphate and concentrated. The crudethus obtained was purified by combiflash column in (gradient: 0-30%EtOAc in DCM) to afford tert-butyl3-oxo-4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazine-1-carboxylate(5) (500 mg, 23.71% yield). LC MS: ES+ 472.6.

Step 3: Synthesis of6-[[4-[(2-oxopiperazin-1-yl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one;hydrochloride: Dioxane-HCl (10 mL) was added to tert-butyl3-oxo-4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazine-1-carboxylate(5) (500 mg, 1.06 mmol) and stirred at rt for 3 hours. After completionof the reaction (monitored by TLC) the reaction mixture was concentratedto dryness and triturated with ether to afford6-[[4-[(2-oxopiperazin-1-yl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one;hydrochloride (6) (400 mg, 71% yield). LC MS: ES+ 372.4.

Step 4: Synthesis of3-methyl-4-[3-oxo-4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile:To a stirred solution of6-[[4-[(2-oxopiperazin-1-yl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one;hydrochloride (6) (400 mg, 980.65 umol) and 3,4-difluorobenzonitrile (7)(136.41 mg, 980.65 umol) in NMP (7 mL) was added DIPEA (633.71 mg, 4.90mmol, 854.06 uL) and the reaction was stirred at 80° C. for 16 hours.After completion of the reaction (monitored by TLC) the reaction mixturewas diluted with ethyl acetate and washed with water and brine, driedover sodium sulfate and concentrated. The crude was purified bycombiflash column (Gradient 50-100% EtOAc in hexane) to afford3-methyl-4-[3-oxo-4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile(8) (150 mg, 29.86% yield) as yellow solid. LC MS: ES+ 491.01.

Step 5: Synthesis of4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6yl]methyl]phenyl]methyl]-3-oxo-piperazin-1-yl]-3-fluoro-benzonitrile: Toa stirred solution of3-fluoro-4-[3-oxo-4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile(8) (150 mg, 305.79 umol) in THF (10 mL) was added Sodium hydride 60%dispersion in mineral oil (70.30 mg, 3.06 mmol) portion wise at 0° C.and stirred for 10 min at RT. The reaction mixture was again cooled to0° C. and 3-bromopiperidine-2,6-dione (9) (293.58 mg, 1.53 mmol) wasadded and the reaction was stirred at 70° C. for 30 min. Aftercompletion of the reaction (monitored by TLC) the reaction mixture wasquenched in ice and extracted with ethyl acetate. The organic part wasfurther washed with water and brine, dried over sodium sulfate andconcentrated. The crude thus obtained was purified by Prep TLC Palte in30% EtOAc in DCM to afford4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]-3-oxo-piperazin-1-yl]-3-fluoro-benzonitrileCompound 172 (85 mg, 46.05% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.33 (d, J=8.28 Hz, 1H), 8.07 (d, J=6.96 Hz,1H), 7.80 (t, J=7.64 Hz, 1H), 7.74-7.70 (m, 1H), 7.56 (d, J=8.36 Hz,1H), 7.40 (d, J=7.36 Hz, 1H), 7.27 (d, J=7.96 Hz, 1H), 7.16 (d, J=7.96Hz, 1H), 7.13-7.09 (m, 2H), 5.43 (dd, J=12.84, 4.92 Hz, 1H), 4.50 (s,2H), 4.38 (s, 2H), 3.91 (s, 2H), 3.49-3.46 (m, 2H), 2.97-2.90 (m, 1H),2.78-2.72 (m, 1H), 2.69-2.62 (m, 1H), 2.10-2.09 (m, 1H) LC MS: ES+602.01.

Example 85. Synthesis of[4-[4-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]disulfanyl]pyrazol-1-yl]-1-piperidyl]-(1-methylcyclobutyl)methanone(Compound 173)

Step 1: Synthesis of 2-benzylsulfanylpropanedial: To a stirred solutionof of phenylmethanethiol (1) (10 g, 80.51 mmol), 2-bromopropanedial (2)(12.76 g, 84.54 mmol) in DMF (80 mL) was added Potassium carbonate(12.24 g, 88.56 mmol) and the resultant reaction mixture was stirred at55° C. for 5 hour. After completion (monitored by TLC) the reactionmixture was diluted with ethyl acetate and washed with water and brine,dried over sodium sulphate and concentrated under reduced pressure toafford 2-benzylsulfanylpropanedial (3) (9 g, 51.79% yield) as brownsolid. LC MS: ES− 192.8.

Step 2: Synthesis of 4-benzylsulfanyl-1H-pyrazole: To a stirred solutionof [benzyl(formyl)-$1{circumflex over ( )}{4}-sulfanyl]formaldehyde (3)(9 g, 49.39 mmol) in Methanol (90 mL) was added hydrazine; hydrate (2.47g, 49.39 mmol, 2.40 mL) and the resultant reaction mixture was heated at90° C. for 16 h. After completion of the reaction (monitored by TLC) thereaction mixture was concentrated under reduced pressure. The crudecrude was then diluted with EtOAc and washed with water and brine, driedover sodium sulphate and concentrated under reduced pressure. Crude thusobtained was purified by Combiflash column (0-20% EtOAc in Hexane) toafford 4-benzylsulfanyl-1H-pyrazole (4) (7 g, 73.01% yield) as gummysolid. LC MS: ES+ 191.1.

Step 3: Synthesis of tert-butyl4-(4-benzylsulfanylpyrazol-1-yl)piperidine-1-carboxylate: To a stirredsolution of compound 4-benzylsulfanyl-1H-pyrazole (4) (3.5 g, 18.40mmol) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (5)(5.14 g, 18.40 mmol) in DMF (20 mL) was added Cesium carbonate (17.98 g,55.19 mmol) and the resultant reaction mixture was heated at 90° C. for16 hours. After completion (monitored by TLC) the reaction mixture wasdiluted with EtOAc and washed with water and brine, dried over sodiumsulphate and concentrated under reduced pressure. The crude thusobtained Organic layer was dried over sodium sulphate concentrated underreduced pressure. Crude thus obtained was purified by Combi-flash column(Gradient: 0-15% EtOAc in Hexane) afforded desired compound tert-butyl4-(4-benzylsulfanylpyrazol-1-yl)piperidine-1-carboxylate (6) (4.5 g,62.22% yield) as light yellow solid. LC MS: ES+ 374.2.

Step 4: Synthesis of 4-(4-benzylsulfanylpyrazol-1-yl)piperidine;Hydrochloride salt: To a stirred solution of compound tert-butyl4-(4-benzylsulfanylpyrazol-1-yl)piperidine-1-carboxylate (6) (7 g, 18.74mmol) in Dioxane (15 mL) was added Dioxane-HCl (4M; 50 mL) and theresultant reaction mixture was stirred at room temperature for 5 hour.After completion of the reaction (monitored by TLC) the reaction masswas concentrated under reduced pressure and triturated with ether toafford 4-(4-benzylsulfanylpyrazol-1-yl)piperidine; Hydrocloride salt (7)(4.5 g, 79.92% yield) as off white solid. LC MS: ES+ 274.4.

Step 5: Synthesis of[4-(4-benzylsulfanylpyrazol-1-yl)-1-piperidyl]-(1-methylcyclobutyl)methanone:To a stirred solution of 4-(4-benzylsulfanylpyrazol-1-yl)piperidine;hydrochloride (7) (4.5 g, 14.52 mmol) and 1-methylcyclobutanecarboxylicacid (1.66 g, 14.52 mmol) in DMF (50 mL) was added DIPEA (9.38 g, 72.61mmol, 12.6 5 mL) and stirred for 15 minutes at RT followed by theaddition of HATU (6.63 g, 17.43 mmol). The resultant reaction mixturewas then allowed to stir at RT for 16 h. After completion of thereaction (monitored by TLC and LC MS) the reaction mixture was dilutedwith ethyl acetate and washed with water and brine, dried over sodiumsulphate and concentrated under reduced pressure. The crude thusobtained was purified by column chromatography (Silica; gradient 0-2%MeOH in DCM) to afford[4-(4-benzylsulfanylpyrazol-1-yl)-1-piperidyl]-(1-methylcyclobutyl)methanone(8) (5 g, 91.31% yield) as light yellow solid. LC MS: ES+ 370.0.

Step 6: Synthesis of[4-[4-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]disulfanyl]pyrazol-1-yl]-1-piperidyl]-(1-methylcyclobutyl)methanone:To a stirred solution of[4-(4-benzylsulfanylpyrazol-1-yl)-1-piperidyl]-(1-methylcyclobutyl)methanone(8) (3 g, 8.12 mmol) intoluene (50 mL) was added Aluminum chloride,Anhydrous (3.25 g, 24.36 mmol, 1.33 mL) and the resultant reactionmixture was stirred at RT for 16 hours. TLC showed some unreacted SMbeing present the reaction mixture was heated at 80° C. for another 4hours. After completion (monitored by TLC) the reaction mixture wasdiluted with cold water and extracted with EtOAc (Twice). The combinedorganic layer was washed with brine, dried over sodium sulphate andconcentrated under reduced pressure. The crude thus obtained waspurified by column chromatography (Gradient 0-2% MeOH in DCM) to afford[4-[4-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]disulfanyl]pyrazol-1-yl]-1-piperidyl]-(1-methylcyclobutyl)methanoneCompound 173 (1.3 g, 25.88% yield) as off white solid. LC MS: ES+ 557.2.

Example 86. Synthesis of3-[6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 174)

Step 1: Synthesis of1-[(4-methoxyphenyl)methyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[cd]indol-2-one:To a stirred solution of6-bromo-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1) (10 g, 27.16mmol) in 1,4 dioxane (200 mL) was added Bis(pinacolato)diboron (10.34 g,40.74 mmol) followed by well dried Potassium Acetate (8.00 g, 81.47mmol). The resultant reaction mass was degassed well with argon for 15minutes. PdCl2(dppf).DCM (2.22 g, 2.72 mmol) was added and the reactionmass was heated at 100° C. for 16 hours. After completion of thereaction (monitored by TLC), the reaction mixture was cooled to RT,filtered through a pad of celite, washed with more Ethyl acetate. Thecombined filtrate was washed with cold water, dried over sodium sulphateand concentrated under reduced pressure. The crude thus obtained waspurified by Combiflash column (gradient 0-15% EtOAc in Hexane) to afford1-[(4-methoxyphenyl)methyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[cd]indol-2-one(2) (10 g, 78% yield) as yellow solid. LC MS: ES+ 416.1.

Step 2: Synthesis of[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]boronic acid: Tothe stirred solution of1-[(4-methoxyphenyl)methyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[cd]indol-2-one(2) (4 g, 9.63 mmol) in Acetone (40 mL) was added a solution of Ammoniumacetate (2.23 g, 28.90 mmol) in Water (20 mL) followed by sodium;periodate (8.24 g, 38.53 mmol). The resultant reaction mixture was thestirred at 70° C. for 18 hours. After completion (monitored by TLC andLCMS) the reaction mass was diluted with cold water and extracted withEtOAc (twice). The combine organic layer was then washed with brine,dried over sodium sulphate and concentrated under reduced pressure. Thecrude thus obtained was purified by combiflash column (Gradient 0-3%MeOH in DCM) to afford[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]boronic acid (3)(2 g, 57.65% yield) as yellow solid. LC MS: ES+ 334.2.

Step 3: Synthesis of1-[(4-methoxyphenyl)methyl]-6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-benzo[cd]indol-2-one:To a stirred solution of[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]boronic acid (3)(299.17 mg, 898.01 umol) and[4-[4-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]disulfanyl]pyrazol-1-yl]-1-piperidyl]-(1-methylcyclobutyl)methanone (9_scheme-1) (500 mg, 898.01 umol) in Ethanol (10mL) was added tetrabutylammonium; hydroxide (2.91 g, 4.49 mmol, 3.20 mL,40% purity). The resultant reaction mixture was degassed with oxygen for10 minute then copper sulphate (28.67 mg, 179.60 umol, 7.96 uL) and1,10-phenanthroline (32.37 mg, 179.60 umol) were added to the reactionmixture was stirred at RT for 16 h. After completion (monitored by TLC)the reaction mixture was filtered through celite pad and washed withethanol and ethyl acetate. The filtrate was concentrated and againdiluted with ethyl acetate and washed with water and brine, dried oversodium sulphate and concentrated under reduced pressure. Crude thusobtained was purified by Combiflash column (Gradient 0-1% MeOH in DCM)to afford1-[(4-methoxyphenyl)methyl]-6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-benzo[cd]indol-2-one(4) (500 mg, 93.34% yield) as light yellow solid. LC MS: ES+ 567.4.

Step 4: Synthesis of6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-1H-benzo[cd]indol-2-one:To the stirred solution of1-[(4-methoxyphenyl)methyl]-6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-benzo[cd]indol-2-one(4) (500 mg, 882.28 umol) in TFA (4 mL) was addedtrifluoromethanesulfonic acid (662.05 mg, 4.41 mmol, 387.16 uL) and theresultant reaction mixture was stirred at RT for 16 hours. Aftercompletion of the reaction (monitored by TLC) the reaction mass wasquenched with saturated bicarbonate solution and extracted with ethylacetate (twice). The combined organic layer was washed with brine, driedover sodium sulphate concentrated under reduced pressure. Crude thusobtained was purified by combiflash column (Gradient 0-3% MeOH in DCM)to afford6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-1H-benzo[cd]indol-2-one(5) (300 mg, 75.38% yield) as light yellow solid. LC MS: ES+ 447.1.

Step 5: Synthesis of3-[6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a cooled solution of6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-1H-benzo[cd]indol-2-one(5) (200 mg, 417.92 umol) in dry THF (3 mL), Sodium hydride (60%dispersion in mineral oil) (15.44 mg, 671.80 umol) was added portionwise, maintaining the temp <5° C. Once the addition is over, theresultant mixture was stirred for 15 minutes at RT. Then the reactionmixture was again cooled to 0° C. and 3-bromopiperidine-2,6-dione (6)(64.50 mg, 335.90 umol) was added to it portion wise. After completeaddition, resulting solution was heated at 60° C. for 30 min. Aftercompletion (evidenced from TLC), the reaction mixture was cooled to 0°C. and quenched with the addition of ice cooled water. Aqueous part wasextracted with ethyl acetate (3×100 mL). Combined organics wasseparated, dried over sodium sulfate and concentrated under reducedpressure. Crude mass was purified by Prep TLC Plate (30% EtOAc in DCM)to afford3-[6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 174 (15 mg, 38% yield) as light yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.48 (d, J=8.28 Hz, 1H), 8.20 (s, 1H), 8.15(d, J=7.0 Hz, 1H), 7.91 (t, J=7.64 Hz, 1H), 7.65 (s, 1H), 7.33 (d,J=7.48 Hz, 1H), 7.08 (d, J=7.56 Hz, 1H), 5.42 (dd, J=12.48, 4.92 Hz,1H), 4.45-4.39 (m, 2H), 3.63-3.62 (m, 1H), 3.11-3.10 (m, 1H), 2.93-2.89(m, 1H), 2.72-2.61 (m, 3H), 2.43-2.40 (m, 2H), 2.10-2.00 (m, 3H),1.95-1.78 (m, 5H), 1.62-1.59 (m, 1H), 1.35 (s, 3H); LC MS: ES+ 558.4.

Example 87. Synthesis of3-[6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfonyl-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione,(Compound 175)

Step 1: Synthesis of6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfonyl-1H-benzo[cd]indol-2-one:To a stirred solution of6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-1H-benzo[cd]indol-2-one(1) (300 mg, 671.80 umol) in Water (1 mL) and Methanol (2 mL) was addedOxone (1.24 g, 2.02 mmol) and the resultant reaction mixture was stirredat RT for 16 hours. After completion of the reaction (monitored by TLC)the reaction mixture was passed through celite pad and washed withEtOAc. The filtrate was then washed with cold water and brine. Theorganic part was dried over sodium sulphate and concentrated underreduced pressure. The crude thus obtained was purified by combiflashcolumn (Gradient 0-2% MeOH in DCM) to afford6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfonyl-1H-benzo[cd]indol-2-one(2) (200 mg, 61.40% yield) as light yellow solid. LC MS ES+ 479.1.

Step 2: Synthesis of3-[6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfonyl-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a cooled solution of6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfonyl-1H-benzo[cd]indol-2-one(2) (200 mg, 417.92 umol) in dry THF (10 mL), Sodium hydride (60%dispersion in mineral oil) (96.08 mg, 4.18 mmol) was added portion wise,maintaining the temp <5° C. Once the addition is over, the resultantmixture was stirred for 15 minutes at RT. Then the reaction mixture wasagain cooled to 0° C. and 3-bromopiperidine-2,6-dione (3) (401.22 mg,2.09 mmol) was added to it portion wise. After complete addition,resulting solution was heated at 60° C. for 30 min. After completion(evidenced from TLC), the reaction mixture was cooled to 0° C. andquenched with the addition of ice cooled water. Aqueous part wasextracted with ethyl acetate (3×100 mL). Combined organics wasseparated, dried over sodium sulphate and concentrated under reducedpressure. Crude mass was purified by Prep TLC Plate (30% EtOAc in DCM)to afford3-[6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfonyl-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 175 (50 mg, 19.2% yield) as light yellow solid. ¹H NMR (400MHz, DMSO-d6) δ 11.18 (s, 1H), 8.79 (d, J=8.32 Hz, 1H), 8.70 (s, 1H),8.29 (d, J=7.8 Hz, 1H), 8.21 (d, J=6.84 Hz, 1H), 8.06 (s, 1H), 7.99 (t,J=7.6 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 5.52-5.49 (m, 1H), 4.43-4.41 (m,1H), 3.58-3.57 (m, 1H), 3.07-3.06 (m, 1H), 2.94-2.90 (m, 1H), 2.78-2.64(m, 3H), 2.41-2.38 (m, 2H), 2.14-2.12 (m, 1H), 1.98-1.87 (m, 3H),1.78-1.76 (m, 4H), 1.69-1.59 (m, 1H), 1.33 (s, 3H); LC MS: ES+ 590.5.

Example 88. Synthesis of4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile(Compound 176)

Step 1: Synthesis of6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfinyl-1H-benzo[cd]indol-2-one:To a stirred solution of6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfanyl-1H-benzo[cd]indol-2-one(1) (300 mg, 671.80 umol) in DCM (20 mL) was added3-chlorobenzenecarboperoxoic acid (69.56 mg, 403.08 umol) and theresultant reaction mixture was stirred at RT for 16 hours. Aftercompletion (monitored by TLC) the reaction mixture was diluted with coldwater and extracted with dicholomethane (Twice). The combined organiclayer was dried over sodium sulphate and concentrated under reducedpressure. The crude thus obtained was purified by combiflash Column(Gradient 0-1% MeOH in DCM) to afford6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfinyl-1H-benzo[cd]indol-2-one(2) (200 mg, 63.55% yield) as light yellow solid. LC MS ES+ 463.3.

Step 2: Synthesis of4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile:To an ice cooled solution of6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]sulfinyl-1H-benzo[cd]indol-2-one(2) (170 mg, 367.52 umol) in dry THF (10 mL), Sodium hydride (60%dispersion in mineral oil) (211.23 mg, 9.19 mmol) was added portionwise, maintaining the temp <5° C. Once the addition is over, theresultant mixture was stirred for 15 minutes at RT. Then the reactionmixture was again cooled to 0° C. and 3-bromopiperidine-2,6-dione (3)(352.84 mg, 1.84 mmol) was added to it portion wise. After completeaddition, resulting solution was heated at 60° C. for 30 min. Aftercompletion (evidenced from TLC), the reaction mixture was cooled to 0°C. and quenched with the addition of ice cooled water. Aqueous part wasextracted with ethyl acetate (3×100 mL). Combined organics wasseparated, dried over sodium sulphate and concentrated under reducedpressure. Crude mass was purified by Prep TLC Plate (30% EtOAc in DCM)to afford4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrileCompound 176 (35 mg, 16.6% yield) light yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.10 (br, 1H), 8.40-8.39 (m, 1H), 8.26-8.20 (m, 1H), 8.16(d, J=6.96 Hz, 1H), 8.09 (d, J=6.84 Hz, 1H), 7.87-7.85 (m, 1H), 7.67 (s,1H), 7.39-7.37 (m, 1H), 5.52-5.50 (m, 1H), 4.43-4.42 (m, 2H), 3.58-3.57(m, 1H), 3.05-2.92 (m, 3H), 2.78-2.75 (m, 1H), 2.69-2.63 (m, 2H),2.44-2.38 (m, 2H), 2.13-2.12 (m, 1H), 1.94-1.89 (m, 3H), 1.79-1.77 (m,3H), 1.61-1.59 (m, 1H), 1.33 (s, 3H); LC MS: ES+ 574.2.

Example 89. Synthesis of3-[6-[[1-(3-benzyloxycyclobutyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 177)

Step 1: Synthesis of1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole:To a stirred solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol e 1 (5.00 g,25.78 mmol) intoluene (60 mL) and 3,4-dihydro-2H-pyran (4.55 g, 54.13mmol, 4.92 mL) under nitrogen condition. To the reaction mixture,2,2,2-trifluoroacetic acid (88.17 mg, 773.30 umol, 59.58 uL) was addedand heated at 80° C. for 4 hours. Reaction mixture was quenched withsaturated solution of Sodium bicarbonate and extracted with ethylacetate. Separated organic layer, dried over sodium sulphate. Filteredand concentrated under reduced pressure. Crude mass was purified bycolumn chromatography to afford1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole2 (7.1 g, 24.25 mmol, 94.07% yield, 95% purity) as yellow oil. LCMS: ES+279.1.

Step 2: Synthesis of1-[(4-methoxyphenyl)methyl]-6-[(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]benzo[cd]indol-2-one:To the stirred solution of6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 3 (1 g,2.96 mmol) and1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole2 (1.32 g, 4.74 mmol) in a sealed tube intoluene (4 mL) and Ethanol (2mL) and 4 drops water were added tripotassium; phosphate (1.57 g, 7.40mmol). It was degassed with argon for 10 minutes. tris-o-tolylphosphane(180.21 mg, 592.07 umol) and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one;palladium (271.08 mg, 296.03 umol) were added to the reaction mixture.It was heated at 90° C. for 16 hours. Reaction mixture was cooled toroom temperature, diluted with ethyl acetate and water, and layers wereseparated. The organic layer was washed with water, brine, dried oversodium sulphate and concentrated under reduced pressure. It was purifiedby column chromatography eluting at 40% ethyl acetate in hexane toafford1-[(4-methoxyphenyl)methyl]-6-[(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]benzo[cd]indol-2-one4 (550 mg, 1.15 mmol, 38.92% yield, 95% purity) as yellow solid. LC MS:ES+ 454.1.

Step 3: Synthesis of 6-(1H-pyrazol-4-ylmethyl)-1H-benzo[cd]indol-2-one:To a stirred solution of1-[(4-methoxyphenyl)methyl]-6-[(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]benzo[cd]indol-2-one4 (550 mg, 1.21 mmol) in TFA (4 mL) was added trifluoromethanesulfonicacid (1.46 g, 9.70 mmol, 851.48 uL) at room temperature then reactionmixture was stirred at room temperature for over night. After checkedTLC (Rf=0.2 in 5% MeOH/DMF) it showed one polar spot was formed andstarting material was consumed then reaction mixture was concentratedunder reduced pressured to get crude mass which diluted with EtOAc andsaturated solution of NaHCO₃, layers were separated. Combined organiclayer was washed with saturated brine solution and dried under vacuumpump to afford 6-(1H-pyrazol-4-ylmethyl)-1H-benzo[cd]indol-2-one 5 (280mg, 1.11 mmol, 91.70% yield, 99% purity) as yellow solid. LCMS: ES+250.3.

Synthesis of (3-benzyloxycyclobutyl) methanesulfonate: To a stirredsolution of 3-benzyloxycyclobutanol (100 mg, 561.08 umol) in DCM (5 mL)was added Triethylamine (113.55 mg, 1.12 mmol, 156.41 uL), cooled thereaction mixture to 0° C. followed by drop wise addition of Methanesulfonyl chloride (77.13 mg, 673.30 umol, 52.11 uL) then reactionmixture was stirred at room temperature for 4 hours. After completion ofSM, reaction mass was diluted with water and extracted with DCM, washedwith saturated solution of NaHCO₃, brine, dried over anhydrous sodiumsulphate and evaporate under reduced pressure to give the crude compound(3-benzyloxycyclobutyl) methanesulfonate 6 (100 mg, 370.63 umol, 66.06%yield, 95% purity) as orange liquid, which was used in next step withoutfurther purification. LCMS: ES+ 257.2.

Step 4: Synthesis of6-[[1-(3-benzyloxycyclobutyl)pyrazol-4-yl]methyl]-1H-benzo 2-one: To astirred solution of 6-(1H-pyrazol-4-ylmethyl)-1H-benzo[cd]indol-2-one 5(115 mg, 461.35 umol) and (3-benzyloxycyclobutyl) methanesulfonate 6(130.08 mg, 507.49 umol) in DMF (10 mL) was added Cesium carbonate(450.95 mg, 1.38 mmol) at room temperature then reaction mixture washeated 80° C. over night. After completion of starting material thenreaction mixture was diluted with cooled water extracted with ethylacetate. Combined organic layer was washed with saturated brine solutionand dried under reduced pressure to get crude which was purified bycombiflash chromatography using 30-40% EtOAc-Hexane as eluent to afford6-[[1-(3-benzyloxycyclobutyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one7 (18 mg, 40.44 umol, 8.77% yield, 92% purity) as light yellow solid. LCMS: ES+ 410.2.

Step 5: Preparation of3-[6-[[1-(3-benzyloxycyclobutyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To the stirred solution of6-[[1-(3-benzyloxycyclobutyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one7 (40.00 mg, 97.69 umol) in THF (3 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (37.43 mg, 976.85 umol, 60%purity) at cold condition and the reaction mixture was stirred at RT for10 minutes followed by portion wised addition of3-bromopiperidine-2,6-dione 8 (93.78 mg, 488.43 umol) and the reactionwas heated at 70° C. for 1 hours. After completion of reaction (by TLC),the reaction mixture was diluted with ethyl acetate and washed withwater, organic fraction separated. It was dried over anhydrous sodiumsulphate and evaporated under reduced pressure to obtain the crude whichwas purified by Prep TLC using 20% EtOAc-DCM as eluent to afford3-[6-[[1-(3-benzyloxycyclobutyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 177 (14.0 mg, 25.42 umol, 26.03% yield, 94.54% purity) as lightyellow solid. ¹H NMR (d6-DMSO, 400 MHZ) d 10.98 (s, 1H), 8.20 (d, J=8.20Hz, 1H), 8.02 (d, J=6.92 Hz, 1H), 7.80 (t, J=7.68 Hz, 1H), 7.55 (s, 1H),7.39-7.29 (m, 8H), 5.27-5.23 (m, 1H), 5.19-5.15 (m, 1H), 4.47 (s, 2H),4.46-4.43 (m, 1H), 4.21 (s, 2H), 3.04-2.97 (m, 2H), 2.75-2.72 (m, 1H),2.70-2.61 (m, 3H), 2.45-2.41 (m, 1H), 2.15-2.14 (m, 1H); LC MS: ES+521.2.

Example 90. Synthesis of3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 178) &3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 179)

Step 1: Preparation of6-[[1-(1-spiro[3.4]octan-8-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one](3): To the stirred solution of6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (1) (500mg, 1.50 mmol) in dry grade THF (12 mL) was added Triethylamine (304.42mg, 3.01 mmol, 419.32 uL) followed by the addition ofspiro[3.4]octan-8-one 2 (186.79 mg, 1.50 mmol), Dibutyltindichloride(548.47 mg, 1.81 mmol, 403.29 uL) and Phenylsilane (162.77 mg, 1.50mmol, 185.39 uL). After complete the reaction mixture was heated at 90°C. for 16 hours in sealed tube. After completion of reaction (monitoredby LC MS), the he reaction mixture was cooled to rt and diluted withethyl acetate (30 mL). Combined organic phase was washed with sodiumbicarbonate solution, water (2×20 mL) and brine (30 ml). The organicfraction was separated, dried over anhydrous sodium sulphate andevaporated under reduced pressure to obtain the crude compound which waspurified by flash chromatography (silica, gradient: 0-5% MeOH in DCM) toafford6-[[1-(1-spiro[3.4]octan-8-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(3) (26 mg, 56.06 umol, 3.73% yield, 95% purity) as yellow solid. LC MS:ES+ 441.6.

Step 2: Chiral separation: Preparation6-[[1-(1-spiro[3.4]octan-8-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(3a) and6-[[1-(1-spiro[3.4]octan-8-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(3b): 80 mg of6-[[1-(1-spiro[3.4]octan-8-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(3) was separated into enantiomers by chiral normal phase PreparativeHPLC method. Prep fractions were first evaporated separately underreduced pressure to obtain solid mass. The solid was then suspended in amixture of Acetonirile and Water (2:3) and it was kept in aDry-ice/Acetone bath until the Acetonitrile-Water mixture solidified.The frozen mixture was then freeze dried under lyophilizer for 20 hoursto afford6-[[1-(1-spiro[3.4]octan-8-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(3a) (first eluted peak, RT=5.31 min, assigned tentatively as ‘S’ ABS)(26 mg, % ee 96.46) and6-[[1-(1-spiro[3.4]octan-8-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(3b) (second eluted peak, RT=6.32 min, assigned tentatively as ‘R’ ABS)(25 mg, % ee 96.86) as yellow solids which were stored in a roundbottomed flask at ambient temperature. LC MS: ES+ 441.6.

Step 3: Synthesis of3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione&3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione:To a cooled solution of6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(3a) (25.00 mg, 56.74 umol) in dry THF (4 mL), Sodium hydride 60%dispersion in mineral oil (13.05 mg, 567.44 umol) was added portionwise, maintaining the temp <5° C. Once the addition is over, theresultant mixture was stirred for 15 minutes at RT. Then the reactionmixture was again cooled to 0° C. and 3-bromopiperidine-2,6-dione (4)(54.48 mg, 283.72 umol) was added to it portion wise. After completeaddition, resulting solution was heated at 70° C. 1 hr. After completion(evidenced from TLC), the reaction mixture was cooled to 0° C. andquenched with the addition of ice cooled water. Aqueous part wasextracted with ethyl acetate (3×50 mL). Combined organics was separated,dried over sodium sulfate and concentrated under reduced pressure. Crudemass was purified by PREP-TLC (gradient: 5% MeOH in DCM) to afford3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 178 (17.0 mg, 28.21 umol, 49.71% yield, 91.54% purity) asyellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ11.11 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83(t, J=7.52 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J=7.24 Hz, 1H), 7.29 (s, 1H),7.07 (d, J=7.28 Hz, 1H), 5.44 (dd, J=11.92, 4.48 Hz, 1H), 4.36 (s, 2H),3.96 (m, 1H), 2.94-2.91 (m, 1H), 2.84-2.82 (m, 2H), 2.66-2.63 (m, 2H),2.49-2.30 (m, 4H), 2.09-2.07 (m, 2H), 1.88-1.74 (m, 8H), 1.60-1.52 (m,5H), 1.32-1.30 (m, 1H); LC MS: ES+ 552.3. To a cooled solution of6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(3b) (25.00 mg, 56.74 umol) in dry THF (4 mL), Sodium hydride 60%dispersion in mineral oil (13.05 mg, 567.44 umol) was added portionwise, maintaining the temp <5° C. Once the addition is over, theresultant mixture was stirred for 15 minutes at RT. Then the reactionmixture was again cooled to 0° C. and 3-bromopiperidine-2,6-dione (4)(54.48 mg, 283.72 umol) was added to it portion wise. After completeaddition, resulting solution was heated at 70° C. 1 hour. Aftercompletion (evidenced from TLC), the reaction mixture was cooled to 0°C. and quenched with the addition of ice cooled water. Aqueous part wasextracted with ethyl acetate (3×50 mL). Combined organics was separated,dried over sodium sulfate and concentrated under reduced pressure. Crudemass was purified by PREP-TLC (gradient: 5% MeOH in DCM) to afford3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-8-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 179 (18.0 mg, 30.76 umol, 54.22% yield, 94.29% purity) asyellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.0Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.44 Hz, 1H), 7.58 (s, 1H),7.35 (d, J=7.36 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.44(dd, J=12.84, 5.08 Hz, 1H), 4.36 (s, 2H), 3.96 (m, 1H), 2.94-2.91 (m,1H), 2.83-2.72 (m, 2H), 2.66-2.63 (m, 2H), 2.49-2.30 (m, 4H), 2.09-2.06(m, 2H), 1.88-1.67 (m, 8H), 1.56-1.52 (m, 5H), 1.32-1.30 (m, 1H); LC MS:ES+ 552.3.

Example 91. Synthesis of3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 180)

Step 1: Synthesis of tert-butyl4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-3-yl]piperidine-1-carboxylate:To a stirred solution of6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (int-A)(500.00 mg, 1.48 mmol) and tert-butyl4-(1H-pyrazol-3-yl)piperidine-1-carboxylate (1) (372 mg, 1.48 mmol) inDMF (5 mL) was added Cesium carbonate (1.21 g, 3.70 mmol) at roomtemperature and the resultant reaction mixture was heated at 90° C. for16 h. After completion (monitored by TLC) the reaction mixture wasdiluted with ethyl acetate and washed with water and brine, dried oversodium sulphate and concentrated under reduced pressure. The crude thusobtained was purified by combiflash Column (Gradient 20-30% EtOAc inHexane) to afford tert-butyl4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-3-yl]piperidine-1-carboxylate(2) (400 mg, 43.03% yield) as light yellow solid. LC MS: ES+ 553.5.

Step 2: Synthesis of1-[(4-methoxyphenyl)methyl]-6-[[3-(4-piperidyl)pyrazol-1-yl]methyl]benzo[cd]indol-2-one;hydrochloride: To a stirred solution of tert-butyl4-[1-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-3-yl]piperidine-1-carboxylate(2) (400 mg, 723.77 umol) in Dioxane (5 mL) was added Dioxane-HCl (4M)(10 mL) under cooling condition and the resultant reaction mixture wasstirred at RT for 4 hours. After completion (monitored by TLC) thereaction mixture was concentrated under reduced pressure. The crude wastriturated with Ether-Pentane to afford1-[(4-methoxyphenyl)methyl]-6-[[3-(4-piperidyl)pyrazol-1-yl]methyl]benzo[cd]indol-2-one;hydrochloride (3) (300 mg, 70.9% Yield) as light yellow solid. LC MS:ES+ 453.4.

Step 3: Synthesis of1-[(4-methoxyphenyl)methyl]-6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]benzo[cd]indol-2-one:To the stirred solution of1-[(4-methoxyphenyl)methyl]-6-[[3-(4-piperidyl)pyrazol-1-yl]methyl]benzo[cd]indol-2-one;hydrochloride (3) (300 mg, 613.49 umol) and1-methylcyclobutanecarboxylic acid (4) (70.02 mg, 613.49 umol) in DMF(10 mL) was added DIPEA (396.44 mg, 3.07 mmol, 534.28 uL) and stirredfor 15 minutes followed by the addition of HATU (279.92 mg, 736.19 umol)and was allowed to stir for 16 hr at RT. After completion (monitored byLCMS), the reaction mixture was diluted with Ethyl acetate and washedwith cold water, brine, dried over sodium sulfate and concentrated underreduced pressure. The crude thus obtained was purified by columnchromatography (silica, gradient: 0-3% MeOH in DCM) to afford1-[(4-methoxyphenyl)methyl]-6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]benzo[cd]indol-2-one(5) (300 mg, 84.6% yield) as gummy solid. LC MS: ES+ 549.5.

Step 4 and 4a: Synthesis of6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]ethyl]-1H-benzo[cd]indol-2-one&6-[[5-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of compound1-[(4-methoxyphenyl)methyl]-6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]benzo[cd]indol-2-one(5) (250 mg, 455.64 umol) in TFA (3 mL) was addedTrifluoromethanesulfonic acid (341.91 mg, 2.28 mmol, 199.95 uL) undercooling condition and the resultant reaction mixture was stirred at RTfor 16 hours. After completion (monitored by TLC) the reaction mixturewas concentrated under reduced pressure and crude mass was basified withsaturated sodium bicarbonate solution and extracted with ethyl acetate.The layers were separated and the organic part was dried over sodiumsulphate and concentrated under reduced pressure. Crude thus obtainedwas purified by Combiflash column (Gradient 0-3% MeOH in DCM) to affordcompound (6) (150 mg) as regiomeric mixture. This regiomeric mixture wasseparated by Preparative HPLC which was done on Waters auto purificationinstrument. Column name: Kinetex Evo C18 (250×20 mm, 5μ) operating atambient temperature and flow rate of 16 mL/min. Mobile phase: A=10 mMAmmonium Acetate in water, B=Acetonitrile; Gradient Profile: Mobilephase initial composition of 90% A and 10% B, then 65% A and 35% B in 3min, then to 50% A and 50% B in 25 min., then to 100% B in 25.5 min.,held this composition up to 27.5 min. for column washing, then returnedto initial composition in 28 min. and held till 30 min to afford desiredcompound6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one(7) (55 mg, 27.04% yield) as yellow solid and6-[[5-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one(7a) (30 mg, 15.06% yield) as yellow solid. LC MS: ES+ 429.4.

Step 5: Synthesis of3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one(7) (50 mg, 116.68 umol) in THF (5 mL) was added Sodium hydride 60%dispersion in mineral oil (8.05 mg, 350.04 umol) at 0° C. and stirredfor 5 min. Then 3-bromopiperidine-2,6-dione (8) (44.81 mg, 233.36 umol)was added under cooling condition and the reaction mixture was stirredat 70° C. for 60 min. After completion (monitored by TLC) the reactionmixture was quenched in ice and extracted with ethyl acetate. Theorganic part was further washed with water and brine, dried over sodiumsulfate and concentrated. The crude was purified by Prep TCL Plate in30% Acetone in DCM to afford3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 180 (17 mg, 26.4% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.13 (s, 1H), 8.42 (d, J=8.28 Hz, 1H), 8.10 (d, J=6.96 Hz,1H), 7.85 (t, J=7.56 Hz, 1H), 7.72 (s, 1H), 7.41 (d, J=7.20 Hz, 1H),7.13 (d, J=7.28 Hz, 1H), 6.09 (s, 1H), 5.86 (s, 2H), 5.47-5.44 (m, 1H),4.32-4.28 (m, 1H), 3.54-3.50 (m, 1H), 3.02-2.91 (m, 2H), 2.80-2.73 (m,2H), 2.66-2.63 (m, 2H), 2.42-2.34 (m, 2H), 2.09-2.07 (m, 2H), 1.91-1.77(m, 5H), 1.61-1.58 (m, 1H), 1.42-1.38 (m, 1H), 1.32 (s, 3H).LC MS: ES+540.5.

Example 92. Synthesis of3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxo-imidazolidin-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 181)

Step-1: Synthesis of tert-butyl4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]-2-oxo-imidazolidin-1-yl]piperidine-1-carboxylate:To a stirred solution of tert-butyl4-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (1) (318.93 mg, 1.18mmol) in THF (10 mL) was added Sodium hydride 60% dispersion in mineraloil (54.45 mg, 2.37 mmol) at room temperature and the resultant reactionmixture was stirred at RT for 30 minutes. Then6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (int-A)(400 mg, 1.18 mmol) was added and the reaction mixture was allowed tostir at RT for 16 h. After completion (monitored by TLC) the reactionmixture was quenched with crushed ice and was extracted with EtOAc(Twice). The combined organic layer was further washed with water andbrine, dried over sodium sulphate and concentrated under reducedpressure. The crude thus obtained was purified by combiflash column(Gradient 0-3% MeOH in DCM) to afford tert-butyl4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]-2-oxo-imidazolidin-1-yl]piperidine-1-carboxylate(2) (320 mg, 28.41% yield) as light yellow solid. LC MS ES+ 571.6.

Step-2: Synthesis of1-[(4-methoxyphenyl)methyl]-6-[[2-oxo-3-(4-piperidyl)imidazolidin-1-yl]methyl]benzo[cd]indol-2-one;hydrochloride: To a stirred solution of tert-butyl4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]-2-oxo-imidazolidin-1-yl]piperidine-1-carboxylate(2) (300 mg, 525.69 umol) in Dioxane (5 mL) was added Dioxane-HCl (4M)(10 mL) under cooling condition and the resultant reaction mixture wasstirred at RT for 4 hours. After completion (monitored by TLC) thereaction mixture was concentrated under reduced pressure. The crude wastriturated with Ether-Pentane to afford1-[(4-methoxyphenyl)methyl]-6-[[2-oxo-3-(4-piperidyl)imidazolidin-1-yl]methyl]benzo[cd]indol-2-one;hydrochloride (3) (250 mg, 83.13% Yield) as off white solid. LC MS: ES+471.1.

Step-3: Synthesis of1-[(4-methoxyphenyl)methyl]-6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxo-imidazolidin-1-yl]methyl]benzo[cd]indol-2-one:To the stirred solution of1-[(4-methoxyphenyl)methyl]-6-[[2-oxo-3-(4-piperidyl)imidazolidin-1-yl]methyl]benzo[cd]indol-2-one;hydrochloride (3) (250 mg, 493.07 umol) and1-methylcyclobutanecarboxylic acid (4) (56.28 mg, 493.07 umol) in DMF (2mL) was added DIPEA (318.62 mg, 2.47 mmol, 429.41 uL) and stirred for 15minutes followed by the addition of HATU (224.98 mg, 591.69 umol) andwas allowed to stir for 16 hr at RT. After completion (monitored byLCMS), the reaction mixture was diluted with Ethyl acetate and washedwith cold water, brine, dried over sodium sulfate and concentrated underreduced pressure. The crude thus obtained was purified by columnchromatography (silica, gradient: 0-3% MeOH in DCM) to afford1-[(4-methoxyphenyl)methyl]-6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxo-imidazolidin-1-yl]methyl]benzo[cd]indol-2-one(5) (220 mg, 72.81% yield) as light yellow solid. LC MS: ES+ 567.6.

Step-4: Synthesis of6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxo-imidazolidin-1-yl]methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of1-[(4-methoxyphenyl)methyl]-6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxo-imidazolidin-1-yl]methyl]benzo[cd]indol-2-one(5) (200 mg, 352.93 umol) in TFA (3 mL) was addedtrifluoromethanesulfonic acid (264.84 mg, 1.76 mmol, 154.88 uL) undercooling condition. Then the reaction mixture was stirred at roomtemperature for 16 hr. After completion (monitored by TLC and LCMS) thereaction mass was quenched with saturated bicarbonate solution andextracted with ethyl acetate (twice). The combined organic part wasdried over Sodium sulphate and concentrated under reduced pressure. Thecrude thus obtained was purified by combiflash Column (Gradient 0-3%MeOH in DCM) to afford6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxo-imidazolidin-1-yl]methyl]-1H-benzo[cd]indol-2-one(6) (100 mg, 57.11% yield) as light yellow solid. LC MS: ES+ 447.2.

Step-5: Synthesis of3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxo-imidazolidin-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxo-imidazolidin-1-yl]methyl]-1H-benzo[cd]indol-2-one(6) (90 mg, 201.55 umol) in THF (5 mL) was added Sodium hydride 60%dispersion in mineral oil (13.90 mg, 604.65 umol) at 0° C. and stirredfor 5 min. Then 3-bromopiperidine-2,6-dione (7) (77.40 mg, 403.10 umol)was added under cooling condition and the reaction mixture was stirredat 70° C. for 30 min. After completion (monitored by TLC) the reactionmixture was quenched in ice and extracted with ethyl acetate. Theorganic part was further washed with water and brine, dried over sodiumsulfate and concentrated. The crude was purified by Prep TCL Plate in30% Acetone in DCM to afford3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]-2-oxo-imidazolidin-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 181 (17 mg, 13.9% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.45 (d, J=8.36 Hz, 1H), 8.10 (d, J=6.84 Hz,1H), 7.86 (t, J=7.36 Hz, 1H), 7.43 (d, J=7.28 Hz, 1H), 7.11 (d, J=7.32Hz, 1H), 5.46-5.43 (m, 1H), 4.67 (s, 2H), 4.50-4.46 (m, 1H), 3.89-3.70(m, 1H), 3.60-3.50 (m, 1H), 3.16-2.10 (m, 4H), 3.02-2.92 (m, 2H),2.77-2.73 (m, 1H), 2.67-2.63 (m, 2H), 2.39-2.34 (m, 2H), 2.11-2.08 (m,1H), 1.90-1.80 (m, 1H), 1.80-1.70 (m, 2H), 1.65-1.55 (m, 3H), 1.55-1.45(m, 2H), 1.32 (s, 3H). LC MS: ES+ 558.3.

Example 93. Synthesis of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(Compound 182)

Step-1: Synthesis of 6-bromo-1H-benzo[cd]indol-2-one (2): To a stirredsuspension of 1H-benzo[cd]indol-2-one (1) (250 g, 1.48 mol) inChloroform (2.5 L), a solution of molecular bromine (354.23 g, 2.22 mol,113.53 mL) in Chloroform (500 mL) was added drop wise at 0° C. and thereaction mixture was stirred at room temperature for 16 hours. Aftercompletion of the reaction (monitored by TLC), the reaction mass waspoured into saturated aqs. solution of Sodium thiosulphate. The yellowsolid formed was filtered through sintered funnel, washed with water,pentane and stripped with toluene to afford6-bromo-1H-benzo[cd]indol-2-one (2) (350 g, 90% yield) as yellow solid.LC MS: ES+ 2 (248.2 and 250.2).

Step-2: Synthesis of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one:To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (2) (100 g,403.10 mmol) in 1,4 dioxane (1 L) was added Bis(pinacolato)diboron(153.55 g, 604.66 mmol) followed by well dried Potassium Acetate (118.68g, 1.21 mol, 75.60 mL). The resultant reaction mass was degassed wellwith argon for 15 minutes. PdCl2(dppf).DCM (32.92 g, 40.31 mmol) wasadded and the reaction mass was heated at 100° C. for 16 hours. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wascooled to RT, filtered through a pad of celite, washed with more Ethylacetate. The combined filtrate was washed with cold water, dried oversodium sulphate and concentrated under reduced pressure to afford6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-oneCompound 182 (110 g, 64% yield) as brown gum. LC MS: ES+ 295.7.

Example 94. Synthesis of4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6yl]methyl]phenyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile (Compound183, Compound 184, and (Compound 185)

Step-1: Synthesis of tert-butyl4-(4-cyano-2-fluoro-phenyl)piperazine-1-carboxylate (3): To a stirredsolution of 3,4-difluorobenzonitrile (1) (13 g, 93.46 mmol) in DMSO (80mL), Potassium carbonate (19.37 g, 140.18 mmol, 8.46 mL) and tert-butylpiperazine-1-carboxylate (2) (19.15 g, 102.80 mmol) were added and theresultant reaction mixture was heated at 100° C. for 16 hours. Aftercompletion (monitored by TLC), the reaction mixture was allowed to cooland water (500 ml) was added to it. The solid that formed was filteredoff, washed with water, and dried under vacuum to obtain tert-butyl4-(4-cyano-2-fluoro-phenyl)piperazine-1-carboxylate (3) (20 g, 66%yield) as a white solid. LC MS: ES+ 306.2.

Step-2: Synthesis of 3-fluoro-4-piperazin-1-yl-benzonitrileHydrochloride salt (4): To a stirred solution of tert-butyl4-(4-cyano-2-fluoro-phenyl)piperazine-1-carboxylate (3) (20 g, 65.50mmol) in Dioxane (15 mL) was added Dioxane-HCl (65.50 mmol, 50 mL) andthe reaction mixture was stirred at RT for 3 hours. All the volatileswere removed under reduced pressure. The solid obtained was trituratedwith ether to afford 3-fluoro-4-piperazin-1-yl-benzonitrile;hydrochloride (4) (17 g, 88% yield) as a white solid. LC MS: ES+ 206.4.

Step-3: Synthesis of4-[4-[[4-(chloromethyl)phenyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile(6): To a stirred solution of 3-fluoro-4-piperazin-1-yl-benzonitrile;hydrochloride (4) (15 g, 62.06 mmol) in DMF (75 mL) was added DIPEA(24.06 g, 186.19 mmol, 32.43 mL) and the reaction mixture was stirredfor 5 minutes. Then 1,4-bis(chloromethyl)benzene (5) (10.86 g, 62.06mmol, 7.65 mL) was added in one portion and the reaction was heated at60° C. for 16 hours. After completion (monitored by TLC), the reactionmixture was diluted with ethyl acetate and washed with water and brine,dried over sodium sulfate and concentrated. The crude thus obtained waspurified by column chromatography (silica, gradient: 10-30% EtOAc inHexane) to afford4-[4-[[4-(chloromethyl)phenyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile(6) (7 g, 32% yield) as a white solid. LC MS: (Es, ES+ 2) 344.2, 346.4.

Step-4: Synthesis of3-fluoro-4-[4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile(7): To a well degassed solution of4-[4-[[4-(chloromethyl)phenyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile(6) (7 g, 20.36 mmol) and6-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-benzo[cd]indol-2-one (3)(9.08 g, 30.54 mmol) in ethanol (30 mL) and Toluene (60 mL), Potassiumphosphate tribasic, anhydrous, (10.80 g, 50.90 mmol) was added followedby the addition of Tri-o-Tolyl phosphine (1.24 g, 4.07 mmol) andPd2(dba)3 (1.86 g, 2.04 mmol). The resulting mixture was then heated at100° C. for 16 hours. After completion of reaction (as monitored byLCMS), the reaction mixture was filtered through a bed of celite, washedwith Ethyl acetate. The combined filtrate was washed with water andbrine, dried over sodium sulfate and concentrated under reducedpressure. Crude mass was purified by column chromatography (silica,gradient: 0-40% Ethyl acetate in Hexane) to obtain3-fluoro-4-[4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile (7) (5.5 g, 52% yield,)as yellow solid. LC MS: ES+ 477.4.

Step-5: Synthesis of4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6yl]methyl]phenyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile: To acooled solution offluoro-4-[4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile(7) (5.5 g, 11.54 mmol) in dry THF (30 mL), Sodium hydride (60%dispersion in mineral oil) (2.65 g, 115.41 mmol) was added portion wise,maintaining the temp <5° C. Once the addition is over, the resultantmixture was stirred for 15 minutes at RT. Then the reaction mixture wasagain cooled to 0° C. and 3-bromopiperidine-2,6-dione (8) (11.08 g,57.71 mmol) was added to it portion wise. After complete addition,resulting solution was heated at 70° C. 1 hour. After completion(evidenced from TLC), the reaction mixture was cooled to 0° C. andquenched with the addition of ice cooled water. Aqueous part wasextracted with ethyl acetate (3×100 mL). Combined organics wasseparated, dried over sodium sulfate and concentrated under reducedpressure. Crude mass was purified by column chromatography (silica,gradient: 30-100% EtOAc in DCM) to afford4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrileCompound 183 (4.4 g, 63% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.28 Hz, 1H), 8.07 (d, J=6.92 Hz,1H), 7.80 (t, J=7.66 Hz, 1H), 7.66 (d, J=12.4 Hz, 1H), 7.54 (d, J=8.36Hz, 1H), 7.40 (d, J=7.28 Hz, 1H), 7.26-7.19 (m, 4H), 7.11-7.05 (m, 2H),5.44 (dd, J=12.64, 4.84 Hz, 1H), 4.37 (s, 2H), 3.49 (s, 2H), 3.12 (br s,4H), 2.98-2.90 (m, 1H), 2.79-2.73 (m, 1H), 2.70-2.62 (m, 1H), 2.45 (brs, 4H), 2.10-2.07 (m, 1H); LC MS: ES+ 588.48.

Step-6 (Chiral separation): Preparation of4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrileand4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile:4.4g of4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrileCompound 183 was separated into enantiomers by chiral SFC method toafford4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrileCompound 184 (1.5g, % ee 100) and4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrileCompound 185 (1.55 g, % ee 100) as yellow solids.

Example 95. Synthesis of-(6-((1-(3,3-difluoro-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 186) and3-(6-((1-(3,3-difluoro-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 187)

Step 1: Synthesis of obtain tert-butyl4-(2-tert-butoxycarbonylhydrazino)-3,3-difluoro-piperidine-1-carboxylate(2): Mixture solution of tert-butyl3,3-difluoro-4-oxo-piperidine-1-carboxylate (1) (3.0 g, 12.75 mmol) andtert-butyl N-aminocarbamate (1.69 g, 12.75 mmol) in Acetic acid (13 mL)was stirred at rt for 2 hours. After that, Sodium cyanoborohydride (1.04g, 16.58 mmol) was added to the reaction mixture and stirring wascontinued for 12 hours at room temperature. After completion of reaction(evidenced from TLC), volatiles were removed under reduced pressure.Resulting Sticky solid was then quenched with 5 N NaOH to maintain pH-9.Aqueous part was extracted with DCM (2×50 mL), separated, dried overanhydrous sodium sulfate and concentrated under reduced pressure toobtain crude tert-butyl4-(2-tert-butoxycarbonylhydrazino)-3,3-difluoro-piperidine-1-carboxylate(2) (4.11 g, 9.36 mmol, 73.37% yield). LC MS: ES+ 352.1.

Step-2: Synthesis of ethyl1-(3,3-difluoro-4-piperidyl)pyrazole-4-carboxylate; hydrochloride (4):To the mixture solution of tert-butyl4-(2-tert-butoxycarbonylhydrazino)-3,3-difluoro-piperidine-1-carboxylate(2) (4.11 g, 11.70 mmol) and ethyl 2-formyl-3-oxo-propanoate (3) (1.69g, 11.70 mmol) in Ethanol (72 mL), 4M dioxane-HCl (38 mL) was added dropwise at rt. After complete addition, RM was heated at 75° C. for 5hours. After completion of reaction (evidenced from LC MS), volatileswere removed under reduced pressure. Resulting brown gummy solid wasquenched with saturated sodium bicarbonate solution. Aqueous part wasextracted with ethyl acetate (2×50 mL), separated, dried over anhydroussodium sulfate and concentrated to afford ethyl 1-(3,3-difluoro-4-piperidyl)pyrazol e-4-carboxylate; hydrochloride (4) (3.0 g,7.23 mmol, 61.77% yield) which was directly used in the next stepwithout any purification. LC MS: ES+ 260.4.

Step-3: Synthesis of tert-butyl4-(4-ethoxycarbonylpyrazol-1-yl)-3,3-difluoro-piperidine-1-carboxylate(5): To the stirred solution of ethyl1-(3,3-difluoro-4-piperidyl)pyrazole-4-carboxylate; hydrochloride (4)(3.0 g, 10.14 mmol) in dry grade THF (10.0 mL) was added Triethylamine,99% (2.05 g, 20.29 mmol, 2.83 mL) and Di-tert-butyl dicarbonate (6.64 g,30.43 mmol, 6.98 mL) at 0° C. and after complete addition the reactionmix was stirred at rt for 12 hours. After completion of reaction(monitored by LC MS), volatiles were removed and resulting reaction masswas redissolved in ethyl acetate (50 mL). Organic phase was washed withwater (40 mL)/brine (30 mL), separated, dried over anhydrous sodiumsulfate and concentrated. Crude thus obtained was purified by columnchromatography (silica, gradient: 0-40% Ethyl acetate in Hexane) toafford tert-butyl4-(4-ethoxycarbonylpyrazol-1-yl)-3,3-difluoro-piperidine-1-carboxylate(5) (2.6 g, 7.16 mmol, 70.60% yield) as sticky solid which was stored ina round bottomed flask at 5° C. inside a refrigerator. LC MS: ES+ 304.2(M-56).

Step 4: Synthesis of tert-butyl3,3-difluoro-4-[4-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate(6): To the stirred solution of tert-butyl4-(4-ethoxycarbonylpyrazol-1-yl)-3,3-difluoro-piperidine-1-carboxylate(5) (1.0 g, 2.78 mmol) in dry grade THF (10.0 mL), Diisobutylaluminumhydride (7.91 g, 13.91 mmol, 9.22 mL) was added drop wise at −78° C. andstirred for 4 hours at same temperature under N₂ atmosphere. Aftercomplete consumption, as evidenced from TLC, reaction mass was dilutedwith ethyl acetate (30 mL) and quenched with water (20 mL). Organicphase was separated, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford tert-butyl3,3-difluoro-4-[4-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate(6) (857 mg, 2.62 mmol, 94.14% yield) as yellow gum which was carriedforward to the next step without any further purification. LC MS: ES+318.1.

Step-5: Synthesis of tert-butyl4-[4-(chloromethyl)pyrazol-1-yl]-3,3-difluoro-piperidine-1-carboxylate(7): N,N-Diisopropylethylamine (2.61 g, 20.17 mmol, 3.51 mL) neat wasadded by syringe to a stirred solution of tert-butyl3,3-difluoro-4-[4-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate(6) (1.6 g, 5.04 mmol) in dry grade DCM (17 mL) at 0° C. under nitrogenatmosphere, followed by Methanesulfonyl chloride, 98% (1.44 g, 12.61mmol, 975.63 uL) neat by syringe and stirred the reaction mix at rt for16 hours. After completion of reaction (evidenced from TLC), thereaction was diluted to 50 ml DCM and washed with 2N HCl (10 mL).Organic phase was further washed with saturated sodium bicarbonatesolution and separated, dried over anhydrous sodium sulfate andconcentrated to afford tert-butyl4-[4-(chloromethyl)pyrazol-1-yl]-3,3-difluoro-piperidine-1-carboxylate(7) (1.65 g, 3.93 mmol, 77.97% yield, 80% purity) as brown gummy solidwhich was carried forward to the next step without any furtherpurification. LC MS: ES+ 280.1 (M-56).

Step 6a: Synthesis of tert-butyl3,3-difluoro-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate(9): To a well degassed solution of tert-butyl4-[4-(chloromethyl)pyrazol-1-yl]-3,3-difluoro-piperidine-1-carboxylate(7) (1.74 g, 5.18 mmol and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(8) (20.92 g, 70.89 mmol) in Ethanol (4 mL)-Toluene (8 mL), Potassiumphosphate tribasic, anhydrous, ((3.30 g, 15.55 mmol) was added followedby the addition of Tri-o-Tolyl phosphine (315.45 mg, 1.04 mmol) andPd₂(dba)₃ (474.53 mg, 518.20 umol). The resulting mixture was thenheated at 90° C. for 12 hours. After completion of reaction (asmonitored by LCMS), the reaction mixture was filtered through a bed ofcelite, washed with Ethyl acetate (200 mL). The combined filtrate wasthen washed with water (3×50 mL) and brine (2×40 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Crudemass was purified by column chromatography (silica, gradient: 0-20%Ethyl acetate in DCM) to obtain tert-butyl3,3-difluoro-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate(9) (225 mg, 256.14 umol, 4.94% yield) as yellow solid which was storedin a Tarson plastic bottle at ambient temperature. LC MS: ES+ 469.2.

Step 6b: Chiral separation: Compound was separated by normal phaseChiral HPLC using following method to afford4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoro-piperidine-1-carboxylatecpd-10a (100 mg) and4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoro-piperidine-1-carboxylate10b (100 mg).

Step-7a: Synthesis of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoro-piperidine-1-carboxylate(12a): To a ice cooled solution of3,3-difluoro-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate(100.00 mg, 213.45 umol) (10a) in dry THF (5 mL), Sodium hydride (60%dispersion in mineral oil) (85.38 mg, 2.13 mmol, 60% purity) was addedportion wise, maintaining the temp <5° C. Once the addition is over, theresultant mixture was stirred for 15 minutes at RT. Then the reactionmixture was again cooled to 0° C. and 3-bromopiperidine-2,6-dione (11)(204.92 mg, 1.07 mmol) was added to it portion wise. After completeaddition, resulting solution was heated at 70° C. for 1 hour. Aftercompletion (evidenced from TLC), the reaction mixture was again cooledto 0° C. and quenched with ice cooled water (10 mL). Aqueous part wasextracted with ethyl acetate (2×20 mL). Combined extracts was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Crudemass was purified by flash chromatography (silica, gradient: 2.5% MeOHin DCM) to tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoro-piperidine-1-carboxylate(12a) (100 mg, 167.36 umol, 78.41% yield, 97% purity) as yellow solid asyellow solid which was stored in a round bottomed flask at 5° C. insidea refrigerator; LC MS: ES+ 580.4.

Step-7b: Synthesis of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd[indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoro-piperidine-1-carboxylate(12b): To a stirred solution of tert-butyl3,3-difluoro-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate(10b) (100.00 mg, 213.45 umol) in dry THF (5.0 mL), Sodium hydride (inoil dispersion) 60% dispersion in mineral oil (85.38 mg, 2.13 mmol, 60%purity) was added at 0° C. and stirred for 15 minutes followed by theaddition of 3-bromopiperidine-2,6-dione 11 (204.92 mg, 1.07 mmol).Resulting reaction mixture was stirred at 70° C. for 1.5 hour. As mostof the SM was remain un-reactive as evidenced from TLC and LCMS,reaction mixture was heated to reflux for 2 hours. After completeconversion of SM as evidenced from LCMS, reaction mixture was quenchedwith water and extracted with ethyl acetate (2×20 mL). Combined organiclayer was separated, dried over sodium sulfate and concentrated. Crudereaction mass was purified by PREP-TLC (2.5% MeOH in DCM as eluent) toafford tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoro-piperidine-1-carboxylate(12b) (100 mg, 155.28 umol, 72.75% yield, 90% purity) as yellow solid;LC MS: ES+ 580.4.

Step-8a: Synthesis of3-(6-((1-(3,3-difluoropiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(13a): To a stirred solution of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoro-piperidine-1-carboxylate12a (100 mg, 172.53 umol) in dry dioxane (2.0 mL), dioxane/HCl (172.53umol, 1.0 mL) was added at 0° C. Resulting reaction mixture was stirredat rt for 4 hours. After complete conversion of SM as evidenced fromLCMS, reaction mixture was quenched with sodium bicarbonate solution andextracted with ethyl acetate (2×20 mL). Combined organic layer wasseparated, dried over sodium sulfate and concentrated. Crude reactionmass was washed with diethyl ether to afford3-[6-[[1-[3,3-difluoro-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione13a (82 mg, 157.34 umol, 91.19% yield, 92% purity) as yellow solid.

Step 8b: Synthesis of3-(6-((1-(3,3-difluoropiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(13b): To a stirred solution of tert-butyl(4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-3,3-difluoro-piperidine-1-carboxylate(100 mg, 172.53 umol) in dry dioxane (2.0 mL), dioxane/HCl (172.53 umol,1.0 mL) was added at 0° C. Resulting reaction mixture was stirred at rtfor 4 hours. After complete conversion of SM as evidenced from LCMS,reaction mixture was quenched with sodium bicarbonate solution andextracted with ethyl acetate (2×20 mL). Combined organic layer wasseparated, dried over sodium sulfate and concentrated. Crude reactionmass was washed with diethyl ether to afford3-[6-[[1-[3,3-difluoro-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione13b (60 mg, 120.13 umol, 69.63% yield, 96% purity) as yellow solid.

Step 9a: Synthesis of3-(6-((1-(3,3-difluoro-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To the stirred solution of3-[6-[[1-[3,3-difluoro-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione13a (82.0 mg, 171.02 umol) in THF (12.0 mL) was added1-methylcyclobutanecarbaldehyde 14 (20.14 mg, 205.22 umol), followed bythe addition of Dibutyltindichloride (62.36 mg, 205.22 umol, 45.85 uL)and Phenylsilane (18.51 mg, 171.02 umol). The reaction mixture was thenstirred at 90° C. for 16 hours. Reaction mixture was diluted with ethylacetate, washed with sodium bicarbonate solution, water and brinesolution. The organic fraction was separated. It was dried overanhydrous sodium sulphate, evaporated under reduced pressure to obtainthe crude compound which was purified by flash chromatography using 0-5%MeOH-DCM to afford3-[6-[[1-[3,3-difluoro-1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 186 (25.0 mg, 43.68 umol, 25.54% yield, 98.13% purity) asyellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.28Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.82 (t, J=7.58 Hz, 1H), 7.61 (s, 1H),7.39-7.36 (m, 2H), 7.08 (d, J=7.16 Hz, 1H), 5.44-5.42 (m, 1H), 4.65-4.60(m, 1H), 4.20 (s, 2H), 2.97-2.91 (m, 2H), 2.81-2.62 (m, 3H), 2.42-2.27(m, 5H), 2.10-2.08 (m, 1H), 1.95-1.74 (m, 5H), 1.62-1.60 (m, 2H), 1.14(s, 3H); LC MS: ES+ 562.2.

Step-9b: Synthesis of3-(6-((1-(3,3-difluoro-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To the stirred solution of3-[6-[[1-[3,3-difluoro-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione13b (60.0 mg, 125.14 umol) in THF (12.0 mL) was added followed by theaddition of 1-methylcyclobutanecarbaldehyde 14 (14.74 mg, 150.16 umol),dibutyltindichloride (45.63 mg, 150.16 umol, 33.55 uL) and Phenylsilane(13.54 mg, 125.14 umol). The reaction mixture was then stirred at 90° C.for 16 hours. Reaction mixture was diluted with ethyl acetate, washedwith sodium bicarbonate solution, water and brine solution. The organicfraction was separated. It was dried over anhydrous sodium sulphate,evaporated under reduced pressure to obtain the crude compound which waspurified by flash chromatography using 0-5% MeOH-DCM to afford3-[6-[[1-[3,3-difluoro-1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 187 (5.0 mg, 8.42 umol, 6.73% yield, 94.61% purity) as yellowsolid. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (d, J=8.6 Hz,1H), 8.08 (d, J=7.52 Hz, 1H), 7.85-7.82 (m, 1H), 7.61 (s, 1H), 7.38-7.36(m, 2H), 7.08 (d, J=7.32 Hz, 1H), 5.45-5.42 (m, 1H), 4.63-4.62 (m, 1H),4.20 (s, 2H), 2.94-2.73 (m, 4H), 2.66-2.62 (m, 1H), 2.36-2.27 (m, 3H),2.08-2.06 (m, 1H), 1.95-1.74 (m, 3H), 1.62-1.60 (m, 2H), 1.53-1.52 (m,1H), 1.14 (s, 3H), 0.92-0.85 (m, 2H); LC MS: ES+ 562.3.

Example 96. Synthesis of3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 188), Compound 189, and Compound 190)

Step 1: Synthesis of1-[[4-(chloromethyl)phenyl]methyl]-4-(2-fluorophenyl)piperazine (3): Toa stirred solution of 1-(2-fluorophenyl)piperazine (1) (2 g, 11.10 mmol)in dry grade DMF (5 mL), DIPEA (4.30 g, 33.29 mmol, 5.80 mL) was addedfollowed by 1,4-bis(chloromethyl)benzene (2) (3.89 g, 22.19 mmol, 2.74mL). Resulting reaction mixture was heated at 60° C. for 12 hours. Aftercompletion of reaction (evidenced from LC MS), ice cooled water (25 ml)was added to RM and extracted with ethyl acetate (3×30 mL). Organicportion was separated, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. Crude reaction mass was purified bycolumn chromatography (silica, gradient: 0-40% Ethyl acetate in Hexane)to afford1-[[4-(chloromethyl)phenyl]methyl]-4-(2-fluorophenyl)piperazine (3) (3g, 8.47 mmol, 76.31% yield, 90% purity) as yellow solid; LC MS: ES+319.4.

Step 2: Synthesis of6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(5): To the stirred solution of6-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-benzo[cd]indol-2-one (4)(500 mg, 1.68 mmol) and1-[[4-(chloromethyl)phenyl]methyl]-4-(2-fluorophenyl)piperazine (536.10mg, 1.68 mmol) (3) in Ethanol (1 mL) and Toluene (2 mL) was addedtripotassium; phosphate (892.33 mg, 4.20 mmol) followed by 0.5 ml waterand the reaction mass was degassed under nitrogen atmosphere over 10minutes. Then tris-o-tolylphosphane (102.36 mg, 336.31 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (153.98 mg, 168.15umol) were added to this reaction mass and heated the resultant reactionmixture 90° C. for overnight. After completion of reaction, RM wasfiltered through celite bed, washed with Ethyl acetate (50 mL). Filtratewas collected and washed with water (2×20 mL)/brine (20 mL). Combinedorganic layer was separated, dried over sodium sulfate and concentratedunder vacuum. Crude was purified by column chromatography (silica,gradient: 0-40% Ethylacetate in Hexane) to afford6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(5) (280 mg, 539.49 umol, 32.08% yield, 87% purity) as yellow solid; LCMS: 452.4.

Step 3: Preparation of3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a ice cooled solution of6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one5 (80 mg, 177.17 umol) in dry THF (8 mL), Sodium hydride (in oildispersion) 60% dispersion in mineral oil (67.89 mg, 1.77 mmol, 60%purity) was added portion wise, maintaining the temp <5° C. Once theaddition is over, the resultant mixture was stirred for 15 minutes atRT. Then the reaction mixture was again cooled to 0° C. and3-bromopiperidine-2,6-dione 6 (170.10 mg, 885.87 umol) was added to itportion wise. After complete addition, resulting solution was heated at70° C. for 1 hour. After completion (evidenced from TLC), the reactionmixture was again cooled to 0° C. and quenched with ice cooled water (40mL). Aqueous part was extracted with ethyl acetate (3×50 mL). Combinedextracts were dried over anhydrous sodium sulfate and concentrated underreduced pressure. Crude mass was purified by flash chromatography(silica, gradient: 3% MeOH in DCM) to afford3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 188 (20 mg, 34.69 umol, 19.58% yield, 97.59% purity). 1H NMR(400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.16 Hz, 1H), 8.07 (d,J=6.92 Hz, 1H), 7.81 (t, J=7.92 Hz, 1H), 7.41 (d, J=7.24 Hz, 1H),7.26-7.20 (m, 4H), 7.11-7.05 (m, 3H), 7.0-6.93 (br m, 2H), 5.43 (dd,J=12.64, 4.76 Hz, 1H), 4.38 (s, 2H), 3.45 (s, 2H), 2.96 (br s, 5H),2.76-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.50 (br s, 4H), 2.10-2.09 (m,1H); LC MS: ES+ 563.5.

Step 4: Chiral separation: (Compound 189 and Compound 190): 550 mg of3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 188 was separated into enantiomers by SFC method. Prepfractions were first evaporated separately under reduced pressure toobtain solid mass. The solid was then suspended in a mixture ofAcetonirile and Water (2:3) and it was kept in a Dry-ice/Acetone bathuntil the Acetonitrile-Water mixture solidified. The frozen mixture wasthen freeze dried under lyophilizer for 20 hours to afford3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 189 (96 mg, 165.66 umol, 16.95% yield, 97.09% purity) (firsteluted peak, RT=8.38 min, assigned tentatively as ‘S’ ABS) (96 mg, % ee100)3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(100 mg, 164.78 umol, 16.86% yield, 92.71% purity) Compound 190 (secondeluted peak, RT=11.8 min, assigned tentatively as ‘It’ ABS) (100 mg, %ee 97.4) as yellow solids.

Example 97. Synthesis of3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 191)

Step 1: Synthesis of benzyl 4-(benzoylhydrazono)piperidine-1-carboxylate(3): To the stirred solution of benzyl 4-oxopiperidine-1-carboxylate (1)(5.0 g, 21.44 mmol, 4.27 mL) in dry grade Methanol (30.0 mL),benzohydrazide (2) (2.92 g, 21.44 mmol) was added and resulting solutionwas heated at 70° C. for overnight. After completion of reaction,monitored by LC MS, the reaction mix was evaporated and crude thusobtained was washed with pentane to get the pure benzyl4-(benzoylhydrazono)piperidine-1-carboxylate (3) (7.5 g, 17.07 mmol,79.66% yield); LC MS: ES+ 352.3.

Step 2: Synthesis of benzyl4-(2-benzoylhydrazino)-4-(trifluoromethyl)piperidine-1-carboxylate (5):Allyl(trimethyl)silane (4) (3.66 g, 32.01 mmol, 5.10 mL) and Borontrifluoride diethyl etherate, 98+% (4.54 g, 32.01 mmol, 4.02 mL) wasadded to a stirred solution of benzyl4-(benzoylhydrazono)piperidine-1-carboxylate (3) (7.5 g, 21.34 mmol,856.88 uL) in DCE (40.0 mL). After complete addition, the reaction mixwas gently refluxed for 10 mins. Then the solvent was evaporated undervacuo. After that DMF (10.0 mL) was added to the reaction mass followedby the addition of sodium acetate (7.00 g, 85.37 mmol, 4.58 mL) andtrifluoromethyl trimethyl silane (6.07 g, 42.69 mmol, 6.31 mL) andstirred the reaction mix at room temperature for overnight. Aftercompletion of reaction (evidenced from TLC), ice cooled water (20 mL)was added to the reaction mix and the reaction mix was extracted withethyl acetate (3×50 mL) and washed with brine solution (2×40 ml).Organic part was separated, dried over anhydrous Na₂SO₄ and concentratedunder vacuum. Resulting crude reaction mass was purified by flashchromatography (gradient: 0-40% Ethyl acetate in Hexane) to affordbenzyl4-(2-benzoylhydrazino)-4-(trifluoromethyl)piperidine-1-carboxylate (5)(5.94 g, 14.10 mmol, 66.04% yield) as colorless solid and stored in around bottomed flask at ambient temperature; LC MS: ES+ 422.1.

Step 3: Synthesis of ethyl1-[4-(trifluoromethyl)-4-piperidyl]pyrazole-4-carboxylate (7): Solutionof benzyl4-(2-benzoylhydrazino)-4-(trifluoromethyl)piperidine-1-carboxylate (5)(5.94 g, 14.08 mmol) and ethyl 2-formyl-3-oxo-propanoate (6) (2.03 g,14.08 mmol) in Ethanol (87 mL), 4(M)dioxane-HCl (46 mL) was added dropwise fashion. After complete addition, reaction mixture is heated at 75°C. for 16 hours. After completion of reaction, monitored by LC MS,volatiles were removed vacuum. Solid reaction mass was partitionedbetween sat NaHCO₃ (pH:7-8) and EtOAc (100 mL). Organic layer is washedwater (50 mL) and brine (50 mL), separated, dried over MgSO₄ andconcentrated under reduced pressure to afford ethyl1-[4-(trifluoromethyl)-4-piperidyl]pyrazole-4-carboxylate (7) (4.0 g,10.30 mmol, 73.13% yield) as brown sticky solid which was stored in around bottomed flask at ambient temperature; LC MS: ES+ 292.0.

Step 4: Synthesis of tert-butyl4-(4-ethoxycarbonylpyrazol-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylate(8): To the stirred solution of ethyl1-[4-(trifluoromethyl)-4-piperidyl]pyrazole-4-carboxylate (7) (4.22 g,14.49 mmol) in THF (10.0 mL), was added Triethylamine, 99% (7.33 g,72.44 mmol, 10.10 mL) followed by Di-tert-butyl dicarbonate (9.49 g,43.46 mmol, 9.98 mL) at 0° C. Resulting solution was stirred at rt for12 hours. Reaction mix was evaporated and the crude compound wasdissolved in ethyl acetate (100 mL). Organic phase was washed with water(2×40 mL) amd brine (50 mL). After separation of organic phase, driedover Na₂SO₄ and evaporated. Crude reaction mass was purified by flashchromatography (gradient: 0-30% Ethyl acetate in Hexane) to affordtert-butyl4-(4-ethoxycarbonylpyrazol-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylate(8) (2.6 g, 6.24 mmol, 43.10% yield) as yellow sticky solid which wasstored in a round bottomed flask at ambient temperature; LC MS: ES−390.25.

Step 5: Synthesis of tert-butyl4-[4-(hydroxymethyl)pyrazol-1-yl]-4-(trifluoromethyl)piperidine-1-carboxylate(9): To the stirred solution of tert-butyl4-(4-ethoxycarbonylpyrazol-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylate(8) (1.0 g, 2.56 mmol) in THF (10 mL), Diisobutylaluminum hydride (7.27g, 12.78 mmol, 10.37 mL, 25% purity) was added drop wise at −78° C. andstirred for 4 hours at rt under N₂ atmosphere. After completeconsumption, as evidenced from TLC, reaction mass was diluted with ethylacetate (50 mL) and quenched with aqueous solution of Sodium Potassiumtartarate (20 mL). Organic phase was separated, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford tert-butyl4-[4-(hydroxymethyl)pyrazol-1-yl]-4-(trifluoromethyl)piperidine-1-carboxylate (9) (890 mg, 2.42 mmol, 94.72%yield) as brown gum which was carried forward to the next step withoutany further purification; LC MS: ES+ 294.2 (M-56).

Step 6: Synthesis of tert-butyl4-(4-formylpyrazol-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylate(10): To a stirred solution of tert-butyl4-[4-(hydroxymethyl)pyrazol-1-yl]-4-(trifluoromethyl)piperidine-1-carboxylate(9) (900 mg, 2.58 mmol) in Acetonitrile (20 mL), was added activatedMnO₂ (2.24 g, 25.76 mmol) and stirred at RT for 24 hours. Aftercompletion of the reaction (monitored by TLC and LC MS), reaction masswas filtered through celite and the filtrate was concentrated underreduced pressure. Crude mass was purified by flash chromatography(gradient: 0-30% Ethyl acetate in Hexane) to afford tert-butyl4-(4-formylpyrazol-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylate 10(630 mg, 1.72 mmol, 66.89% yield) as colorless gummy solid; LC MS: ES+292.1 (M-56).

Step 7: Synthesis of tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-(trifluoromethyl)piperidine-1-carboxylate(12): To the stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (11)(450 mg, 1.81 mmol) in dry grade THF (20.0 mL), was added Phenyllithium,typically 1.8M in di-n-butyl ether (152.45 mg, 1.81 mmol, 188.20 uL) at−78° C. and the reaction was stirred at the same temperature for 30minutes followed by the addition of n-Butyllithium (127.82 mg, 2.00mmol) at same temperature under N₂ atmosphere. After complete addition,the temperature of reaction mixture was allowed to increase to −40° C.and stirred at the same temperature for 30 minutes. After getting thedes-bromo spot in TLC (30% ethyl acetate in Hexane), solution oftert-butyl4-(4-formylpyrazol-1-yl)-4-(trifluoromethyl)piperidine-1-carboxylate(10) (630.05 mg, 1.81 mmol) in dry THF (20.0 mL) was added at −78° C.stirring was continued for 16 hours at room temperature. Reactionmixture was quenched with saturated ammonium chloride solution andextracted with ethyl acetate (2×40 mL). Organic phase was washed withwater (2×20 mL) and separated, dried over anhydrous sodium sulphate andevaporated under reduced pressure to obtain the crude compound which waspurified by flash chromatography (silica, gradient: 0-5% MeOH in DCM) toafford tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-(trifluoromethyl)piperidine-1-carboxylate(12) (225 mg, 370.27 umol, 20.41% yield) as brown solid which was storedin a round bottomed flask at ambient temperature; LC MS: ES+ 517.5.

Step 8: Synthesis of 2,2,2-trifluoroacetate;6-[[1-[4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(13): To the stirred solution of tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-(trifluoromethyl)piperidine-1-carboxylate(12) (223 mg, 431.74 umol) in DCE (2.0 mL) was added triethylsilane(200.81 mg, 1.73 mmol, 275.84 uL) and Trifluoroacetic acid, 99% (393.82mg, 3.45 mmol, 266.09 uL). Resulting solution heated at 70° C. undermicrowave condition for 30 mins. After completion of reaction (evidencedfrom TLC and LC MS), volatiles were removed. Solid residue was redissolved in ethyl acetate (30 mL) and washed with saturated bicarbonatesolution. Organic phase was separated, died over anhydrous sodiumsulfate and concentrated. Crude reaction mass was purified by flashchromatography (gradient: 0-5% MeOH in DCM) to afford2,2,2-trifluoroacetate;6-[[1-[4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(13) (140 mg, 178.50 umol, 41.35% yield) as yellow solid which was keptat ambient temperature in a round bottomed flask; LC MS: ES+ 401.3.

Step 9: Synthesis of6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(15): To the stirred solution of6-[[1-[4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(13) (140 mg, 349.65 umol) in THF (12 mL),1-methylcyclobutanecarbaldehyde (14) (37.75 mg, 384.62 umol) was addedfollowed by the addition of Dibutyltindichloride (127.49 mg, 419.58umol, 93.74 uL) and Phenylsilane (37.84 mg, 349.65 umol, 43.09 uL).Resulting reaction mixture was then heated at 90° C. in a sealed tubefor 16 hours. After completion of reaction (evidenced from TLC), thereaction mixture was diluted with ethyl acetate (20 mL), washed withsodium bicarbonate solution, water (10 mL) and brine (10 mL) solution.The organic portion was separated, dried over anhydrous sodium sulphateand evaporated under reduced pressure to obtain the crude compound whichwas purified by flash chromatography using (gradient: 0-5% MeOH in DCM)to afford6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(15) (45 mg, 74.61 umol, 21.34% yield, 80% purity) as yellow solid whichwas stored at ambient temperature in a round bottomed flask; LC MS: ES+483.4.

Step 10: Synthesis of3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a ice cooled solution of6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(15) (42 mg, 87.04 umol) in dry THF (5 mL), Sodium hydride (60%dispersion in mineral oil) ((33.35 mg, 870.40 umol) was added portionwise, maintaining the temp <5° C. Once the addition is over, theresultant mixture was stirred for 15 minutes at RT. Then the reactionmixture was again cooled to 0° C. and 3-bromopiperidine-2,6-dione (16)(83.56 mg, 435.20 umol) was added to it portion wise. After completeaddition, resulting solution was heated at 70° C. for 1 hour. Aftercompletion (evidenced from TLC), the reaction mixture was again cooledto 0° C. and quenched with ice cooled water (10 mL). Aqueous part wasextracted with ethyl acetate (2×20 mL). Combined extracts was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Crudemass was purified by PREP-TLC (2.5% MeOH in DCM as eluent) to afford3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-(trifluoromethyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 191 (22 mg, 36.88 umol, 42.37% yield) as yellow solid which wasstored in a round bottomed flask at 5° C. inside a refrigerator. 1H NMR(400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.36 (d, J=8.24 Hz, 1H), 8.09 (d,J=7.0 Hz, 1H), 8.02 (s, 1H), 7.81 (t, J=7.76 Hz, 1H), 7.47 (s, 1H), 7.34(d, J=7.24 Hz, 1H), 7.10 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.6, 4.76 Hz,1H), 4.25 (s, 2H), 2.97-2.91 (m, 1H), 2.8-2.67 (br m, 6H), 2.06 (s, 3H),2.0-1.89 (m, 3H), 1.74-1.68 (m, 7H), 0.85 (s, 3H); LC MS: ES+ 594.7.

Example 98. Synthesis of3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 192)

Step 1: Synthesis of tert-butyl 4-azidopiperidine-1-carboxylate (2): Tothe stirred solution of tert-butyl4-methylsulfonyloxypiperidine-1-carboxylate (1) (10 g, 35.80 mmol) indry grade DMF (50.0 mL), was added Sodium azide (9.31 g, 143.19 mmol,5.03 mL) and resulting solution was refluxed at 100° C. for 2 hours.After completion of reaction (evidenced from TLC), the reaction mix waspoured into crushed ice and extracted with Ethyl acetate (2×200 mL).Organic phase was separated, dried over anhydrous sodium sulfate andconcentrated to afford crude tert-butyl 4-azidopiperidine-1-carboxylate(2) (8 g, 33.59 mmol, 93.83% yield, 95% purity) which was directly usedfor the next step without any further purification; LC MS: ES+ 227.2.

Step 2: Synthesis of tert-butyl4-[4-(diethoxymethyl)triazol-1-yl]piperidine-1-carboxylate (3): To thestirred solution of 3,3-diethoxyprop-1-yne (4.5 g, 35.11 mmol) in THF(50 mL), was added tert-butyl 4-azidopiperidine-1-carboxylate (2) (7.94g, 35.11 mmol) followed by aqueous solution (10 mL) of coppersulfatepentahydrate (876.64 mg, 3.51 mmol) and resulting solution was rt for 15mins. After that sodium;(2R)-2-[1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (2.78 g,14.04 mmol) was added to the reaction mixture and stirring was continuedfor further 12 hours at same temperature. After complete consumption ofSM (Monitored by TLC), then the reaction mix was diluted with ethylacetate (100 mL) and filtered through bed of celite. Filtrate wascollected and evaporated under vacuum. Crude thus obtained was purifiedby flash chromatography (silica, gradient: 0-5% MeOH in DCM) to obtaintert-butyl 4-[4-(di ethoxymethyl)triazol-1-yl]piperidine-1-carboxylate(3) (11.54 g, 29.30 mmol, 83.46% yield) which was stored in roundbottomed flask at 5° C. in a refrigerator; LC MS: ES+ 355.3.

Step 3: Synthesis of 1-(4-piperidyl)triazole-4-carbaldehyde;hydrochloride (4): To the stirred solution of tert-butyl4-[4-(diethoxymethyl)triazol-1-yl]piperidine-1-carboxylate (3) (9.5 g,26.80 mmol) in Dioxane (10 mL) 4.0 M in dioxane Hydrogen chloridesolution (977.22 mg, 26.80 mmol, 40.0 mL) was added drop wise at 0° C.and stirred the reaction mix for overnight at rt. After completion ofreaction (evidenced from LC MS), volatiles were removed under reducedpressure. Solid thus obtained was triturated with diethyl ether toafford 1-(4-piperidyl)triazole-4-carbaldehyde; hydrochloride (4) (5.6 g,20.80 mmol, 77.59% yield, 94% purity); LC MS: ES+ 181.2.

Step 4: Synthesis of1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazole-4-carbaldehyde(6): To the stirred solution of 1-methylcyclobutanecarboxylic acid (5)(3.06 g, 26.77 mmol) in dry grade DMF (10.0 mL), was added HATU (339.48mg, 892.82 umol) and stirred for 15 minutes at rt under N₂ atmosphere.Solution of 1-(4-piperidyl)triazole-4-carbaldehyde; hydrochloride (4)(5.8 g, 26.77 mmol) and and N-ethyl-N-isopropyl-propan-2-amine (17.30 g,133.85 mmol, 23.31 mL) in dry grade DMF (3.0 mL) was added to theresulting solution at 0° C. and stirred for another 12 hr at rt. Aftercompletion of reaction (evidenced from LCMS), ice cooled water (5 mL)was added to the reaction mixture and extracted with ethyl acetate (3×70mL). Organic portion was separated, dried over anhydrous sodium sulfateand concentrated. Crude thus obtained was purified by flashchromatography (silica, gradient: 0-5% MeOH in DCM) to obtain1-[1-(1-methylcyclobutanecarbonyl)-4-piperidy]itriazole-4-carbaldehyde 6(4.32 g, 14.23 mmol, 53.14% yield) as yellow solid; LC MS: ES+ 277.3.

Step 5: Synthesis of afford6-[hydroxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(8): To the stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (7)(1.65 g, 6.65 mmol) in dry grade THF (20.0 mL), was added Phenyllithium,1.9M in di-n-butyl ether (559.00 mg, 6.65 mmol, 690.12 uL) at −78° C.under N₂ atmosphere and the reaction was stirred at the same temperaturefor 30 minutes followed by the addition of n-Butyllithium (468.65 mg,7.32 mmol) same temperature. After complete addition, the temperaturewas allowed to increase to −40° C. and the reaction mixture was stirredat the same temperature for 30 minutes. After getting the des-bromo spotin TLC (30% ethyl acetate in Hexane) solution of1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazole-4-carbaldehyde(6) (1.84 g, 6.65 mmol) in dry THF (20.0 mL) was added at −78° C. andstirring was continued for 16 hours at room temperature. Reactionmixture was quenched with saturated ammonium chloride solution andextracted with ethyl acetate (2×50 mL). Organic phase was washed withwater (2×30 mL) and separated, dried over anhydrous sodium sulphate andevaporated under reduced pressure to obtain the crude compound which waspurified by flash chromatography (silica, gradient: 0-5% MeOH in DCM) toafford6-[hydroxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(8) (281 mg, 523.51 umol, 7.87% yield, 83% purity) as brown solid andstored at ambient temperature in a round bottomed flask; LC MS: ES+446.4.

Step 6: Synthesis of6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(9): To the stirred solution of6-[hydroxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(8) (280 mg, 628.49 umol) in DCE (2.0 mL) was added triethylsilane(292.32 mg, 2.51 mmol, 401.54 uL) and Trifluoroacetic acid, 99% (573.28mg, 5.03 mmol, 387.35 uL). Resulting solution heated at 70° C. undermicrowave condition for 30 mins. After completion of reaction (evidencedfrom TLC and LC MS), volatiles were removed. Solid residue was redissolved in ethyl acetate (50 mL) and washed with saturated bicarbonatesolution. Organic phase was separated, died over anhydrous sodiumsulfate and concentrated. Crude reaction mass was purified by flashchromatography (silica, gradient: 0-5% MeOH in DCM) to afford6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(9) (190 mg, 402.55 umol, 64.05% yield) as yellow solid which was keptat ambient temperature in a round bottomed flask. LC MS: ES+ 430.4.

Step 7: Synthesis of3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a ice cooled solution of-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(105 mg, 244.46 umol) (9) in dry THF (10 mL), Sodium hydride (60%dispersion in mineral oil) (56.20 mg, 2.44 mmol) was added portion wise,maintaining the temp <5° C. Once the addition is over, the resultantmixture was stirred for 15 minutes at RT. Then the reaction mixture wasagain cooled to 0° C. and 3-bromopiperidine-2,6-dione (10) (187.76 mg,977.85 umol) was added to it portion wise. After complete addition,resulting solution was heated at 70° C. for 2 hours. After completion(evidenced from TLC), the reaction mixture was again cooled to 0° C. andquenched with ice cooled water (10 mL). Aqueous part was extracted withethyl acetate (3×30 mL). Combined extracts was dried over anhydroussodium sulfate and concentrated under reduced pressure. Crude mass waspurified by flash chromatography (silica, gradient: 2.5% MeOH in DCM) toaffordi3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]triazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 192 (42 mg, 74.95 umol, 30.66% yield) as yellow solid which wasstored in a round bottomed flask at 5° C. inside a refrigerator. H NMR(400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.39 (d, J=8.24 Hz, 1H), 8.09 (d,J=6.96 Hz, 1H), 7.96 (s, 1H) 7.84 (t, J=7.16 Hz, 1H), 7.39 (d, J=7.4 Hz,1H), 7.09 (d, J=7.16 Hz, 1H), 5.43 (dd, J=13.0, 5.24 Hz, 1H), 4.67-4.66(m 1H), 4.41 (br s, 3H), 3.59 (m, 1H), 3.32-3.1 (m, 1H), 2.95-2.91 (m,1H), 2.77-2.62 (m, 3H), 2.41-2.39 (m, 3H), 2.32-2.01 (m, 2H), 1.98-1.77(m, 5H), 1.61-1.58 (m, 1H), 1.33 (s, 3H); LC MS: ES+ 541.5.

Example 99. Synthesis of-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[(1-methylcyclobutyl)methyl]piperidine-4-carbonitrile(Compound 193)

Step 1: Synthesis of tert-butyl4-cyano-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate(2): 1,3-Diiodo-5,5-dimethylhydantoin (180.70 mg, 475.63 umol) was addedto a mixture of tert-butyl4-(hydroxymethyl)-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate(1) (200 mg, 432.40 umol) and TEMPO (3.38 mg, 21.62 umol) in DCM (5.0mL) at r.t. under argon, and the mixture was stirred at room temperatureuntil the alcohol was consumed (1 h). Molecular iodine (164.62 mg,648.59 umol) and 28-30% aq. NH₃ (432.40 umol, 1.0 mL) were added to thereaction mixture at r.t. and the resulting mixture was stirred at sametemperature for 2 h. After completion of reaction (monitored by TLC) thereaction mixture was poured into sat. aq Na₂SO₃ (20 mL) and extractedwith DCM (3×20 mL). The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford tert-butyl4-cyano-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate(2) (45 mg, 96.39 umol, 22.29% yield) which was sufficiently pure andused in the next step; LC MS: ES+ 458.5.

Step 2: Synthesis of tert-butyl4-cyano-4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate(4): To the stirred solution tert-butyl4-cyano-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate(2) (160 mg, 349.71 umol) in dry grade THF (5 mL), Sodium hydride (60%dispersion in mineral oil (134.00 mg, 3.50 mmol, 60% purity) addedportion wise, maintaining the temp <5° C. Once the addition is over, theresultant mixture was stirred for 15 minutes at room temperature. Thenthe reaction mixture was again cooled to 0° C. and3-bromopiperidine-2,6-dione (3) (335.74 mg, 1.75 mmol) was added to itportion wise. After complete addition, resulting solution was heated at70° C. for 1 hour. After completion (evidenced from TLC), the reactionmixture was again cooled to 0° C. and quenched with ice cooled water (20mL). Aqueous part was extracted with ethyl acetate (3×50 mL). Combinedextracts was dried over anhydrous sodium sulfate and concentrated underreduced pressure. Crude mass was purified by preparative TLC(2.5% MeOHin DCM) to afford tert-butyl4-cyano-4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate(4) (90 mg, 147.20 umol, 42.09% yield) as yellow solid; LC MS: ES+569.4.

Step 3: Synthesis of4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-4-carbonitrilehydrochloride (5): 4 M dioxane-HCL (3 mL) was added to the cooledsolution of tert-butyl4-cyano-4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate(4) (90 mg, 158.28 umol) and stirred for 2 hours at room temperature.After completion of reaction (monitored by LC MS) volatiles were removedto afford4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-4-carbonitrilehydrochloride (5) (78 mg, 125.12 umol, 79.05% yield, 81% purity) asyellow solid; LC MS: ES+ 469.39.

Step 4: Synthesis of4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[(1-methylcyclobutyl)methyl]piperidine-4-carbonitrile:To the stirred solution of1-chloro-4-[4-[[1-(2,4-dioxocyclohexyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-4-carbonitrile(5) (70 mg, 138.89 umol) in dry grade THF (12 mL) was added triethylamine (28.11 mg, 277.79 umol, 38.72 uL) followed by the addition of1-methylcyclobutanecarbaldehyde (6) (20.45 mg, 208.34 umol),Dibutyltindichloride (50.64 mg, 166.67 umol, 37.24 uL) and Phenylsilane(15.03 mg, 138.89 umol, 17.12 uL). After complete addition, the reactionmixture was then stirred at 90° C. for 16 hours. Reaction mixture wasdiluted with ethyl acetate (40 mL), and washed with sodium bicarbonatesolution, water (2×20 mL) and brine (25 ml). The organic fraction wasseparated, dried over anhydrous sodium sulphate and evaporated underreduced pressure to obtain the crude compound which was purified byflash chromatography (silica, gradient: 0-5% MeOH in DCM) to afford4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[(1-methylcyclobutyl)methyl]piperidine-4-carbonitrileCompound 193 (38 mg, 68.69 umol, 49.46% yield, 99.54% purity) as yellowsolid stored under Nitrogen Desiccators (“Terra Universal”) atapproximately 22° C. ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.39 (d,J=8.2 Hz, 1H), 8.09 (d, J=6.96 Hz, 1H), 7.92 (s, 1H), 7.83 (t, J=7.56Hz, 1H), 7.51 (s, 1H), 7.37 (d, J=7.32 Hz, 1H), 7.08 (d, J=7.24 Hz, 1H),5.43 (dd, J=12.76, 5.08 Hz, 1H), 4.22 (s, 1H), 2.94-2.62 (m, 6H),2.44-2.07 (m, 9H), 1.93-1.91 (m, 1H), 1.85-1.70 (m, 3H), 1.61-1.56 (m,2H), 1.12 (s, 3H); LC MS: ES+ 551.3.

Example 100. Synthesis of-[6-[[1-[4-(aminomethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 194)

Step 1: Synthesis of[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methylmethanesulfonate (2): To a cooled solution of6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(1) (200 mg, 401.21 umol) in dry grade DCM (5.0 mL),N,N-Diisopropylethylamine (259.27 mg, 2.01 mmol, 349.41 uL) was addeddrop wise and stirred the reaction mix for 10 mins. Methane sulfonylchloride, 98% (91.92 mg, 802.41 umol, 62.11 uL) was added to thereaction at 0° C. It was then stirred at rt for 1 hour. After completionof reaction (Evidenced from TLC) the reaction mix was diluted with DCM(25 ml) and quenched with NaHCO₃ solution. Organic portion was washedwith brine (30 mL) and separated, dried over anhydrous sodium sulfate,evaporated under reduced pressure to afford crude[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methylmethanesulfonate (2) (230 mg, 378.95 umol, 94.45% yield, 95% purity)which was directly used in the next step without any purification (LC MSnot responding).

Step 2: Synthesis of afforddiazonio-[[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]azanide(3): To the stirred solution of6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(2) (80 mg, 160.48 umol) in dry grade DMF (4 mL), Sodium azide (52.16mg, 802.41 umol, 28.20 uL) was added and resulting solution was heatedat 150° C. for 4 hours. After completion of reaction as evidenced fromTLC, reaction mixture was cooled at rt and ice cooled water (10 mL) wasadded to it. Aqueous part was extracted with ethyl acetate (3×30 mL).Organic phase was washed with brine (30 mL), separated, dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford crudediazonio-[[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]azanide(3) (40 mg, 57.31 umol, 35.71% yield, 75% purity) which was directly inthe next step without further purification; LC MS: ES+ 524.4.

Step 3: Synthesis ofdiazonio-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]azanide(5): To the stirred solution of crudediazonio-[[4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]azanide(3) (80 g, 152.82 mmol) in dry grade THF (4 mL), was added Sodiumhydride 60% dispersion in mineral oil (58.55 g, 1.53 mol, 60% purity)was added portion wise, maintaining the temp <5° C. Once the addition isover, the resultant mixture was stirred for 15 minutes at RT. Then thereaction mixture was again cooled to 0° C. and3-bromopiperidine-2,6-dione (4) (146.71 g, 764.08 mmol) was added to itportion wise. After complete addition, resulting solution was heated at70° C. for 1 hour. After completion (evidenced from TLC), the reactionmixture was again cooled to 0° C. and quenched with ice cooled water (40mL). Aqueous part was extracted with ethyl acetate (3×50 mL). Combinedextracts was dried over anhydrous sodium sulfate and concentrated underreduced pressure. Resulting crude solid was washed with ether andpentane to afforddiazonio-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]azanide(5) (60 mg, 71.86 umol, 47.02% yield) as yellow solid; LC MS: ES+ 635.6.

Step 4: Synthesis of tert-butylN-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]carbamate(6): To the stirred solution ofdiazonio-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]azanide(5) (60 mg, 94.55 umol) in Ethanol (4 mL)-ethyl acetate (4 mL),Triethylamine (19.13 mg, 189.09 umol, 26.36 uL) and tert-butoxycarbonyltert-butyl carbonate (30.95 mg, 141.82 umol, 32.55 uL) were addedfollowed by 10 mol % Palladium (40.25 mg, 378.19 umol). Resultingsolution was evacuated and hydrogenated under balloon pressure for 12hours. After completion of reaction (evidenced from LC MS), reactionmixture was filtered through bed of celite and washed with ethyl acetate(50 mL). Filtrate was collected and evaporated. Crude residue waspurified by PREP-TLC (40% Ethyl acetate in Hexane) to afford tert-butylN-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]carbamate(6) (35 mg, 42.96 umol, 45.44% yield, 87% purity) as yellow solid andstored in round bottomed flask at ambient temperature; LC MS: ES+709.65.

Step 5: Synthesis of3-[6-[[1-[4-(aminomethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:4M Dioxane-HCl (2 mL) was added to tert-butylN-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]methyl]carbamate(6) (35 mg, 49.38 umol) at 0° C. and stirred for 3 hours. Aftercompletion of reaction, as evidenced from LCMS, volatiles were removedand resulting solid was triturated with diethyl ether and lyophilised toobtain3-[6-[[1-[4-(aminomethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 194 (22.0 mg, 32.87 umol, 66.55% yield) as yellow solid andstored under Nitrogen Desiccators (“Terra Universal”) at approximately22° C. ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.41 (d, J=8.24 Hz,1H), 8.10 (d, J=6.88 Hz, 1H), 7.92 (s, 1H), 7.85-7.83 (br m, 3H), 7.50(s, 1H), 7.39 (d, J=7.32 Hz, 1H), 7.07 (d, J=7.2 Hz, 1H), 5.46-5.44 (m,1H), 4.24 (s, 1H), 3.95-3.92 (m, 2H), 3.7-3.66 (m, 1H), 3.48-3.47 (m,1H), 3.16 (s, 2H), 2.95 (t, 12.3 Hz, 2H), 2.83-2.50 (br m, 2H), 2.50 (m,2H), 2.09-2.08 (m, 2H), 1.90 (m, 2H), 1.28-1.18 (m, 5H); LC MS: ES+609.5.

Example 101. Synthesis of3-[6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 195)

Step 1: Synthesis of ethyl1-benzyl-4-[tert-butoxycarbonyl-(tert-butoxycarbonylamino)amino]piperidine-4-carboxylate(3): To the solution of Diisopropylamine, 99+% (5.81 g, 57.39 mmol, 8.09mL) in dry grade THF (50.0 mL) was added n-Butyllithium, 1.67M in hexane(2.45 g, 38.26 mmol, 22.56 mL) at −78° C. under argon atmosphere andstirred the reaction mix at −78° C. for 1 hour. Then propyl1-benzylpiperidine-4-carboxylate (1) (10.0 g, 38.26 mmol) was added dropwise to the reaction mix at −78° C. and stirred the reaction mix at thesame temperature. After 1 hour, tert-butyl(NE)-N-tert-butoxycarbonyliminocarbamate (10.20 g, 44.30 mmol) was addedand stirred the reaction at rt for overnight. After completion ofreaction (evidenced from TLC), the reaction mix was diluted withethylacetate (100 mL) and quenched with saturated ammonium chloridesolution. Organic portion was washed with brine and separated, driedover anhydrous sodium sulfate and evaporated under reduced pressure.Resulting crude reaction mass was purified by column chromatography(silica, gradient: 10-30% Ethyl acetate in Hexane) to get the purecompound ethyl1-benzyl-4-[tert-butoxycarbonyl-(tert-butoxycarbonylamino)amino]piperidine-4-carboxylate(3) (10.0 g, 18.84 mmol, 49.25% yield); LC MS: ES+ 478.2.

Step 2: Synthesis of ethyl 1-benzyl-4-hydrazino-piperidine-4-carboxylate(4): To a stirred cooled solution of ethyl1-benzyl-4-[tert-butoxycarbonyl-(tert-butoxycarbonylamino)amino]piperidine-4-carboxylate(3) (30.0 g, 62.82 mmol) in dioxane (100 mL), Dioxane/HCl (62.82 mmol,70 mL) was added drop wise and stirred the reaction mixture at roomtemperature for 16 hours. After completion of reaction (Monitored byLCMS), volatiles were removed under reduced pressure. Resulting solidmaterial was dissolved in (200 mL of 5% MeOH in DCM) and neutralizedwith the addition of amberlite 21. After neutralization (pH 8) it wasfiltered and solid resin was washed with (10% MeOH in DCM) several time.Filtrate was evaporated to afford the crude ethyl1-benzyl-4-hydrazino-piperidine-4-carboxylate (4) (17 g, 56.39 mmol,89.77% yield) as light brown gummy solid which was stored in a roundbottomed glass at 5° C. in refrigerator. The crude was directly used forthe next step without any furthered purification; LC MS: ES+ 278.0.

Step 3: Synthesis of ethyl1-benzyl-4-(4-ethoxycarbonylpyrazol-1-yl)piperidine-4-carboxylate (6):To a stirred solution of ethyl1-benzyl-4-hydrazino-piperidine-4-carboxylate (4) (2.0 g, 7.21 mmol)intoluene (15 mL) was added Ethyl-2-formyl-3-oxopropionate (5) (1.25 g,8.65 mmol) at 0° C. and heated at 100° C. for 6 hours. After completionof reaction (monitored by LC MS) solvent was evaporated and resultinggummy solid was re dissolved in ethyl acetate (50 mL). Organic portionwas washed with water (2×30 mL) and brine (40 mL). After separation oforganic phase, it was dried over anhydrous sodium sulfate andconcentrated and crude thus obtained was purified by columnchromatography (silica, gradient: 10-30% Ethyl acetate in Hexane) to getthe compound ethyl1-benzyl-4-(4-ethoxycarbonylpyrazol-1-yl)piperidine-4-carboxylate (6)(2.0 g, 4.51 mmol, 62.60% yield, 87% purity) as colourless sticky solid(2.0 g, 4.51 mmol, 62.60% yield) which stored in round bottomed flask atambient temperature; LC MS: ES+ 385.9.

Step 4: Synthesis of O1-tert-butyl O4-ethyl4-(4-ethoxycarbonylpyrazol-1-yl)piperidine-1,4-dicarboxylate (7): To thestirred solution of ethyl1-benzyl-4-(4-ethoxycarbonylpyrazol-1-yl)piperidine-4-carboxylate (6)(2.0 g, 5.19 mmol) in EtOH (50 mL)-ethyl acetate (50 mL),tert-butoxycarbonyl tert-butyl carbonate (2.26 g, 10.38 mmol, 2.38 mL)and Triethylamine, 99% (1.58 g, 15.57 mmol, 2.17 mL) was added. Then thereaction mixture was degassed with Argon for 15 minutes followed by theaddition of 20% Palladium on Carbon (1.06 g, 9.98 mmol) and theresultant reaction mixture was stirred under hydrogen atmosphere for 16hours at room temperature. After completion of the reaction (monitoredby TLC and LCMS), the reaction mixture was filtered through a bed ofcelite, washed with ethyl acetate (100 mL). The combined filtrate wasthen washed with water (3×50 mL) and brine (2×40 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Crudemass was purified by column chromatography (silica, gradient: 0-30%Ethyl acetate in Hexane) to obtain desired compound O1-tert-butylO4-ethyl 4-(4-ethoxycarbonylpyrazol-1-yl)piperidine-1,4-dicarboxylate(7) (1.24 g, 3.07 mmol, 59.22% yield) as light brown sticky solid whichstored in round bottomed glass at ambient temperature; LC MS: ES+ 396.5.

Step 5: Synthesis of tert-butyl4-(hydroxymethyl)-4-[4-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate(8): To the cooled solution of 01-tert-butyl 04-ethyl4-(4-ethoxycarbonylpyrazol-1-yl)piperidine-1,4-dicarboxylate (7) (4.43g, 11.20 mmol) in dry grade THF (50.0 mL), Lithium borohydride (2.68 g,123.23 mmol) was added and stirred the solution at room temperature for16 hours under N₂ atmosphere. After complete consumption, as evidencedfrom TLC, reaction mass was diluted with ethyl acetate (100 mL) andquenched with water (50 mL). Organic phase was separated, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to affordtert-butyl4-(hydroxymethyl)-4-[4-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate(8) (3.2 g, 9.76 mmol, 87.15% yield) as colourless sticky solid, storedat ambient temperature in around bottomed flask. LC MS: ES+ 312.3. Thecrude was directly used for next step without any purification.

Step 6: Synthesis of tert-butyl4-(4-formylpyrazol-1-yl)-4-(hydroxymethyl)piperidine-1-carboxylate (9):To a stirred solution of tert-butyl4-(hydroxymethyl)-4-[4-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate(8) (1.7 g, 5.46 mmol) in HPLC grade Acetonitrile (10 mL) was addedactivated dioxomanganese (2.37 g, 27.30 mmol) at rt and the reaction mixwas stirred at rt for 12 hours. After completion of the reaction(monitored by TLC and LC MS), reaction mass was filtered through bed ofcelite, washed with ethyl acetate (100 mL). Filtrate was concentratedunder reduced pressure and thus crude was obtained purified by columnchromatography (100-200 silica; Ethyl acetate in Hexane) to affordtert-butyl4-(4-formylpyrazol-1-yl)-4-(hydroxymethyl)piperidine-1-carboxylate (9)(1.5 g, 4.80 mmol, 87.92% yield) as colourless sticky solid which wasstored in round bottomed flask at 5° C. in refrigerator; LC MS: ES+310.4.

Step 7: Synthesis of4-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate(10): To the stirred solution of tert-butyl4-(4-formylpyrazol-1-yl)-4-(hydroxymethyl)piperidine-1-carboxylate (9)(180 mg, 581.85 umol) in dry DMF (2 mL), Imidazole (79.22 mg, 1.16 mmol)and Triethylamine 176.63 mg, 1.75 mmol, 243.29 uL) were added followedby tert-butyl-chloro-dimethyl-silane (105.24 mg, 698.22 umol, 129.92 uL)at 0° C. Resultant reaction mixture was heated at 50° C. for 3 hours.After complete consumption of SM, as evidenced from TLC, ice cooledwater (5 mL) was added to the reaction mixture and extracted with ethylacetate (3×20 mL). Organic part was separated, dried over anhydroussodium sulfate and evaporated under crude pressure. Crude thus obtainedwas purified by column chromatography (100-200 silica; 0-25% Ethylacetate in Hexane) to afford tert-butyl 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate(10) (150 mg, 318.68 umol, 54.77% yield) as colorless sticky solid whichwas stored in a round bottomed flask at 5° C. in refrigerator; LC MS:ES+ 424.4.

Step 8: Synthesis of tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzopyrazol-1-yl]-4-(trimethylsilyloxymethyl)piperidine-1-carboxylate (12):To the stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (750 mg, 3.02mmol) (11) in super dry THF (5.0 mL) was added Phenyllithium, typically1.9M in di-n-butyl ether (254.09 mg, 3.02 mmol, 313.69 uL) through ovendried syringe at −78° C. under N₂ atmosphere and the reaction wasstirred at the same temperature for 30 minutes. After that,n-Butyllithium, 2.2M in hexane (213.04 mg, 3.33 mmol) was added to it at−78° C. After complete addition, temperature was allowed to increase to−40° C. and the reaction mixture was stirred at the same temperature for30 minutes. After getting the des-bromo [evidenced from TLC (30% ethylacetate in Hexane)] solution of tert-butyl4-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate(10) (1.28 g, 3.02 mmol) in dry THF (5.0 mL) was added at −78° C. andthen the reaction mixture was allowed to warm to room temperature andwas continued for 16 hours. After completion reaction mixture [evidencedfrom TLC], reaction mixture was quenched with saturated ammoniumchloride solution and diluted with ethyl acetate (50 mL). Organicportion was washed with water (2×30 mL), separated, dried over anhydroussodium sulphate and evaporated under reduced pressure to obtain thecrude compound which was purified by flash chromatography (silica,gradient: 0-5% MeOH-DCM) to afford tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-(trimethylsilyloxymethyl)piperidine-1-carboxylate(12) (639 mg, 1.02 mmol, 33.87% yield) as brown solid which stored inround bottomed flask at ambient temperature; LC MS: ES+ 593.4.

Step 9: Synthesis of[4-(hydroxymethyl)-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-piperidyl](13):To a stirred solution of tert-butyl4-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate(12) (639 mg, 1.08 mmol) in DCE (2.0 mL) was added triethylsilane(501.37 mg, 4.31 mmol, 688.69 uL) and Trifluoroacetic acid, 99% (983.25mg, 8.62 mmol, 664.36 uL). Resulting reaction mix was heated at 70° C.under microwave condition for 30 mins. After completion of reaction(evidenced from LC MS and TLC), volatiles were removed under reducedpressure to afford[4-(hydroxymethyl)-4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-1-piperidyl](630 mg, 906.90 umol, 84.13% yield) as yellow solid and stored in around bottomed flask at ambient temperature (13); LC MS: ES+ 477.5.

Step 10: Synthesis of6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(15): To the stirred solution of1-(1,1-difluoroethyl)cyclopropanecarboxylic acid (14) (323.09 mg, 2.15mmol) in dry grade DMF (5.0 mL), HATU (613.74 mg, 1.61 mmol) was addedat 0° C. followed by the mixture solution of6-[[1-[4-(hydroxymethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(13) and N,N-Diisopropylethylamine (695.38 mg, 5.38 mmol, 937.17 uL)under N₂ atmosphere. After complete addition, reaction mixture wasstirred for 16 h at room temperature. After completion of reaction(evidenced from LCMS; Crude LCMS showed desired mass along with diamidation mass peak), ice cooled water (5 mL) was added to the reactionmixture and extracted with ethyl acetate (3×30 mL). Organic portion wasseparated, dried over anhydrous sodium sulfate and concentrated. Crudethus obtained was then re-dissolved in Methanol (10 mL) and stirred withLiOH (1.5 eq) at rt for 30 minutes. After complete consumption ofintermediate, solvent was evaporated and re-dissolved in ethyl acetate(50 mL). Organic portion was washed with water (2×30 mL) and separated,dried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(15) (500 mg, 822.47 umol, 76.43% yield, 82% purity) as brown gummysolid which was sufficiently pure to use in the next step; LC MS: ES+499.4.

Step 11: Synthesis of6-[[1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(16): To the stirred solution of6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(15) (1.0 g, 2.01 mmol) in dry grade DMF (5.0 mL), Triethylamine, 99%(608.97 mg, 6.02 mmol, 838.80 uL) was added at 0° C. followed by theaddition of tert-Butyldimethylsilyl chloride (453.52 mg, 3.01 mmol,559.91 uL). After complete addition, resulting mixture was heated at 60°C. for 1 hr. After completion of reaction [monitored by LCMS, Crude LCMSshowed desired mass peak along with di-TBDMS protected mass), reactionmixture was quenched with the addition of ice cooled water (5 mL).Aqueous part was extracted with ethyl acetate (3×50 mL) and washed withbrine (2×40 mL). Organic portion was separated, dried over anhydroussodium sulfate and concentrated. Thus crude was obtained purified bycolumn chromatography to afford di TBDMS protected product. The crudematerial was then re-dissolved in Ethanol (10 ml) and stirred inpresence of K2CO3 (4 eq) for 30 minutes at rt. After completeconsumption of intermediate, solvent was evaporated and re-dissolved inethyl acetate (100 mL). Organic part was washed with water (2×30 mL0 andseparated, dried over anhydrous sodium sulfate and concentrated toafford6-[[1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(16) (1.0 g, 1.57 mmol, 78.10% yield) which was sufficiently pure andused in the next step; LC MS: ES+ 613.2.

Step 12: Synthesis of3-[6-[[1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(18): To a stirred solution of6-[[1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(16) (200 mg, 326.39 umol) in dry THF (10.0 mL), Sodium hydride 60%dispersion in mineral oil (78.33 mg, 3.26 mmol) was added at 0° C. Oncethe addition is over, the resultant mixture was stirred for 15 minutesat RT. Then the reaction mixture was again cooled to 0° C. and3-bromopiperidine-2,6-dione (17) (313.36 mg, 1.63 mmol) was added to itportion wise. After complete addition, resulting solution was heated at70° C. for 1 hour. After completion (evidenced from TLC), the reactionmixture was again cooled to 0° C. and quenched with ice cooled water (20mL). Aqueous part was extracted with ethyl acetate (2×20 mL). Combinedextracts was dried over anhydrous sodium sulfate and concentrated underreduced pressure. Crude mass was purified by PREP-TLC (2.5% MeOH in DCMas eluent) to afford3-[6-[[1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(18) (120 mg, 149.20 umol, 45.71% yield, 90% purity) as yellow solid; LCMS: ES+ 610.2.

Step 13: Synthesis of3-[6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:4M Dioxane —HCl (2 mL) was added to3-[6-[[1-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(18) (60 mg, 82.89 umol) at 0° C. and stirred for 16 hr at rt. Aftercompletion of reaction as evidenced from LC MS, volatiles were removed.Crude was re dissolved in ethyl acetate (15 mL) and quenched withsaturated sodium bicarbonate solution (maintaining pH-8). Organic partwas separated, dried over sodium sulfate and concentrated under vacuum.Crude was purified by PREP-TLC (5% MeOH in DCM) to afford3-[6-[[1-[4-(hydroxymethyl)-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 195 (30 mg, 47.97 umol, 57.88% yield) as yellow solid andstored under Nitrogen Desiccators (“Terra Universal”) at approximately22° C. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.40 (d, J=8.12 Hz,1H), 8.08 (d, J=6.8 Hz, 1H), 7.84-7.87 (m, 2H), 7.35 (br s, 2H), 7.06(d, J=7.12 Hz, 1H), 5.44 (dd, J=12.52, 4.76 Hz, 1H), 4.94 (s, 1H), 4.21(s, 2H), 4.0-3.98 (br m, 2H), 3.39 (s, 2H), 2.94-2.91 (m, 2H), 2.76-2.73(m, 1H), 2.66-2.62 (m, 1H), 2.38-2.34 (m, 2H), 2.08 (br m, 1H),1.82-1.80 (m, 1H), 1.26-1.25 (m, 2H), 1.51-1.50 (m, 2H); LC MS: ES+610.2.

Example 102. Synthesis of4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]benzoyl]piperazin-1-yl]-3-fluoro-benzonitrile(Compound 196)

Step 1: Synthesis of tert-butyl4-[4-(chloromethyl)benzoyl]piperazine-1-carboxylate (3): To the stirredsolution of tert-butyl piperazine-1-carboxylate (2) (2.0 g, 10.74 mmol)in dry grade DCM (10.0 mL), Triethylamine, 99% (3.26 g, 32.21 mmol, 4.49mL) was added at 0° C. followed by drop wise addition of4-(chloromethyl)benzoyl chloride (1) (2.44 g, 12.89 mmol). Aftercomplete addition, reaction mixture was stirred for 5 hours at roomtemperature. After formation of desired pdt (evidenced from LCMS), RMwas diluted with DCM (30 mL) and quenched with saturated sodiumbicarbonate solution. Organic phase was washed with water (2×15ml)/brine (20 mL) and separated, dried over sodium sulfate andconcentrated. Crude was purified by column chromatography ((silica,gradient: 0-30% Ethyl acetate in Hexane) to afford tert-butyl4-[4-(chloromethyl)benzoyl]piperazine-1-carboxylate (3) (2.2 g, 6.10mmol, 56.84% yield, 94% purity) as a white solid which kept at ambienttemperature in a round bottomed flask. LC MS: ES+ 339.4.

Step 2: Synthesis of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]benzoyl]piperazine-1-carboxylate(5): To a well degassed solution of tert-butyl4-[4-(chloromethyl)benzoyl]piperazine-1-carboxylate (3) (600 mg, 1.77mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(4) (1.05 g, 3.54 mmol) in Ethanol (2 mL)-Toluene (4 mL), Potassiumphosphate tribasic, anhydrous, (1.13 g, 5.31 mmol) was added followed bythe addition of Tri-o-Tolyl phosphine (107.80 mg, 354.16 umol) andPd₂(dba)₃ (162.16 mg, 177.08 umol). The resulting mixture was thenheated at 90° C. for 12 hours. After completion of reaction (asmonitored by LCMS), the reaction mixture was filtered through a bed ofcelite, washed with ethyl acetate (30 mL). The combined filtrate wasthen washed with water (3×15 mL) and brine (2×15 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Crudemass was purified by column chromatography (silica, gradient: 0-20%Ethyl acetate in DCM) to obtain tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]benzoyl]piperazine-1-carboxylate(5) (350 mg, 526.99 umol, 29.76% yield) as yellow solid which was storedin a Tarson plastic bottle at ambient temperature; LC MS: ES+ 472.3.

Step 3: Synthesis of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6yl]methyl]benzoyl]piperazine-1-carboxylate(7): To a ice cooled solution of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]benzoyl]piperazine-1-carboxylate(5) (680 mg, 1.44 mmol) in dry THF (10 mL), Sodium hydride (60%dispersion in mineral oil) (346.10 mg, 14.42 mmol) was added portionwise, maintaining the temp <5° C. Once the addition is over, theresultant mixture was stirred for 15 minutes at RT. Then the reactionmixture was again cooled to 0° C. and 3-bromopiperidine-2,6-dione (6)(1.38 g, 7.21 mmol) was added to it portion wise. After completeaddition, resulting solution was heated at 70° C. for 1 hour. Aftercompletion (evidenced from TLC), the reaction mixture was again cooledto 0° C. and quenched with ice cooled water (10 mL). Aqueous part wasextracted with ethyl acetate (2×20 mL). Combined extracts was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Crudemass was purified by Preparative TLC (gradient: 50% EtOAc in DCM) toafford tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]benzoyl]piperazine-1-carboxylate(7) (500 mg, 532.06 umol, 36.90% yield) as yellow solid which was Tarsonplastic bottle at ambient temperature; LC MS: ES+ 583.4.

Step 4: Synthesis of tert3-[2-oxo-6-[[4-(piperazine-1-carbonyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione;hydrochloride (8): To the stirred solution of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]benzoyl]piperazine-1-carboxylate(7) (500 mg, 858.16 umol) in dry Dioxane (5.0 mL), Dioxane/HCl (858.16umol, 7.0 mL) was added at 0° C. and stirred for 5 hr at rt. Aftercompletion of reaction (evidenced from LC MS) volatiles were removedunder reduced pressure. Solid material thus obtained was triturated withDiethyl ether to afford3-[2-oxo-6-[[4-(piperazine-1-carbonyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione;hydrochloride (8) (450 mg, 615.72 umol, 71.75% yield) as yellow solid;LC MS: ES+ 483.4.

Step 5: Synthesis of4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]benzoyl]piperazin-1-yl]-3-fluoro-benzonitrile:To the well degassed solution of3-[2-oxo-6-[[4-(piperazine-1-carbonyl)phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione;hydrochloride (8) (200 mg, 385.36 umol) in NMP (2.0 mL),N,N-Diisopropylethylamine (298.83 mg, 2.31 mmol, 402.73 uL) was addedfollowed by 3,4-difluorobenzonitrile (9) (80.41 mg, 578.05 umol).Resulting solution was then heated at 110° C. for 12 hr. Aftercompletion of reaction (evidenced from LC MS), RM was cooled to RT andice cooled water (5 mL) was added to it. Aqueous part was extracted withethyl acetate (3×30 mL). Organic phase was separated, dried over sodiumsulfate and concentrated. Crude residue was purified by Preparative TLC(gradient: 40% EtOAc in DCM) to afford4-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]benzoyl]piperazin-1-yl]-3-fluoro-benzonitrileCompound 196 (31.0 mg, 50.25 umol, 13.04% yield) as yellow solid whichwas stored in a round bottomed flask at 5° C. inside a refrigerator. 1HNMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.35 (d, J=8.16 Hz, 1H), 8.08(d, J=6.8 Hz, 1H), 7.82 (t, J=7.36 Hz, 1H), 7.72 (d, J=13.28 Hz, 1H),7.57 (d, J=8.44 Hz, 1H), 7.46 (d, J=7.24 Hz, 1H), 7.38-7.35 (m, 4H),7.13-7.09 (m, 2H), 5.45-5.43 (m, 1H), 4.45 (s, 2H), 3.81 (br, 2H), 3.58(br, 2H), 3.18 (br, 4H), 2.95-2.92 (m, 1H), 2.80-2.62 (m, 2H), 2.07 (m,1H); LC MS: ES+ 600.2.

Example 103. Synthesis of3-[2-oxo-6-[[4-[(3-oxomorpholin-4-yl)methyl]phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 197)

Step-1: Synthesis of4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholin-3-one3: To a stirred solution of morpholin-3-one 2 (3 g, 29.67 mmol) in DCM(100.0 mL), cooled to 0° C., was added sodium hydride (60% dispersion inmineral oil; 3.56 g, 89.03 mmol, 60% purity) and stirred the reactionmix at the same temperature for 30 mins.2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1(10.58 g, 35.61 mmol) was then added and stirred the reaction at rt for16 h. TLC/LC shows complete consumption of SM. The reaction mix was thentaken under ice-cooled condition, and excess NaH was quenched with ice.The organic phase was then washed with water, followed by brine, andfinally dried over anhyd. Na₂SO₄. The solvent was evaporated and theresidue was purified by column chromatography on silica gel (50% EA/Hex)to furnish the desired product4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholin-3-one3 (1.8 g, 5.11 mmol, 17.21% yield, 90% purity) as yellow solid; LCMS(ES+)=318.2 [M+H]⁺.

Step-2: Synthesis of [4-[(3-oxomorpholin-4-yl)methyl]phenyl]boronic acid4: To the stirred solution of4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholin-3-one3 (1.8 g, 5.67 mmol) in Acetone (45 mL)-Water (15 mL), sodium periodate(6.07 g, 28.37 mmol) and ammonium acetate (2.19 g, 28.37 mmol) wereadded at rt and stirred for 16 hr at same temp. After completion ofreaction as monitored by LC MS, DCM was added and washed with water.Organic phase was separated, dried over sodium sulfate and concentratedto afford [4-[(3-oxomorpholin-4-yl)methyl]phenyl]boronic acid 4 (820 mg,3.14 mmol, 55.33% yield, 90% purity) as colorless solid which was usedin next step without further purification.

Step-3: Synthesis of4-[[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]morpholin-3-one6: To a stirred solution of6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 5 (1.44g, 3.40 mmol) and [4-[(3-oxomorpholin-4-yl)methyl]phenyl]boronic acid 4(1.2 g, 5.11 mmol) intoluene (25 mL) in a sealed tube was addedtripotassium phosphate (1.81 g, 8.51 mmol) and degassed for 10 min.Subsequently, Tetrakis(triphenylphosphine)palladium(0) (393.31 mg,340.36 umol) was added and degassed at argon atmosphere for 10 min. Thereaction mixture was heated at 100° C. for 18 h. The reaction mixturewas then allowed to come to RT, filtered over Celite and was washedthoroughly with ethyl acetate. The solvent was evaporated and theresidue was purified by column chromatography on silica gel (eluting 90%EA/Hex-100% EA) to furnish the desired product4-[[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]morpholin-3-one6 (350 mg, 639.51 umol, 18.79% yield, 90% purity) as yellow viscousliquid; LCMS (ES+)=493.3 [M+H]⁺.

Step-4: Synthesis of4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]morpholin-3-one7: To4-[[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]morpholin-3-one6 (300 mg, 609.06 umol) (300 mg, 609.06 umol) in TFA (2 mL) was addedTrifluoromethanesulfonic acid (365.63 mg, 2.44 mmol, 213.82 uL) at rtand stirred for 16 hr at same temp. After complete consumption of SM,reaction mixture was evaporated to remove the excess reagents. It wasdissolved in DCM, and washed with satd. NaHCO₃. Organic portion wasseparated, dried over sodium sulfate and concentrated under reducedpressure to get the residue which was purified by column chromatographyon silica gel (eluting 3% MeOH/DCM) to furnish the desired product4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]morpholin-3-one7 (150 mg, 362.50 umol, 59.52% yield, 90% purity) as brown viscousliquid; LCMS (ES+)=373.2 [M+H]+.

Step-5: Synthesis of3-[2-oxo-6-[[4-[(3-oxomorpholin-4-yl)methyl]phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of4-[[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]morpholin-3-one7 (250 mg, 671.29 umol) in DMF (5 mL), was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (77.17 mg, 2.01 mmol, 60%purity) at 0° C. Then reaction mixture was then heated to 0-60° C. for 1h. 3-bromopiperidine-2,6-dione (154.67 mg, 805.55 umol) was then addedto the reaction mixture (twice within a gap of 1 h), and the heating wascontinued for 16 hr. Due to non-completion of SM, further3-bromopiperidine-2,6-dione (154.67 mg, 805.55 umol) was added andreaction was continued at 60° C. for further 16 h. After that reactionwas quenched with cold water and extracted with ethyl acetate, driedover sodium sulphate, and concentrated under reduced pressure to givethe crude. This crude was purified by first Combi-Flash ColumnChromatography followed by PREP-HPLC to eventually afford the titlecompound3-[2-oxo-6-[[4-[(3-oxomorpholin-4-yl)methyl]phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 197 (30 mg, 61.64 umol, 9.18% yield, 99.34% purity as yellowsolid. LCMS (ES+)=484.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s,1H, D2O Exchangeable), 8.33 (d, J=8 Hz, 1H), 8.07 (d, J=6.8 Hz, 1H),7.83-7.79 (m, 1H), 7.41 (d, J=6.9 Hz, 1H), 7.29-7.27 (m, 2H), 7.16-7.09(m, 3H), 5.45-5.43 (m, 1H), 4.47 (s, 2H), 4.38 (s, 2H), 4.07 (s, 2H),3.76 (m, 2H), 3.19 (m, 2H), 2.95-2.92 (m, 1H), 2.79-2.73 (m, 1H),2.69-2.63 (m, 1H), 2.07 (m, 1H).

Example 104. Synthesis of3-[6-[[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 198)

Step-1: Synthesis of tert-butylN-(tert-butoxycarbonylamino)-N-(1-methylcyclohexyl)carbamate 2: To thewell stirred solution of 1-methylcyclohexene 1 (2.5 g, 26.00 mmol, 3.09mL) in 2-Propanol (50 mL) at 0° C. was added Di-tert-butylazodicarboxylate (8.98 g, 38.99 mmol) andTris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (314.41 mg,519.91 umol) and finally phenylsilane (3.38 g, 31.19 mmol, 3.84 mL). Thereaction mixture was allowed to come to RT and stirred at this temp. for16 h. After complete consumption of SM, reaction mass was evaporated andthe crude residue was purified by column chromatography (1-5% EA/Hex) toafford tert-butylN-(tert-butoxycarbonylamino)-N-(1-methylcyclohexyl)carbamate 2 (1.5 g,3.65 mmol, 14.05% yield, 80% purity).

Step-2: Synthesis of (1-methylcyclohexyl)hydrazine 3: To a stirredsolution of tert-butylN-(tert-butoxycarbonylamino)-N-(1-methylcyclohexyl)carbamate 2 (12.5 g,38.06 mmol) in Dioxane (100 mL) was added Dioxane-HCl (4 M, 190.29 mL)drop wise at 0° C. It was then allowed to come to RT and stirred for 16h. Crude LCMS showed complete consumption of starting material andformation of product. The reaction mass was evaporated to dryness andsubsequently washed thoroughly with pentane eventually to afford(1-methylcyclohexyl)hydrazine 3 (5 g, 11.44 mmol, 30.05% yield, 60%purity) as a white solid; LCMS (ES+)=128.3 [M+H]+.

Step-3: Synthesis of ethyl 1-(1-methylcyclohexyl)pyrazole-4-carboxylate5: To a stirred solution of (1-methylcyclohexyl)hydrazine 3 (7.5 g,46.80 mmol) intoluene (100 mL) was added Ethyl-2-formyl-3-oxopropionate4 (8.09 g, 56.16 mmol) and stirred the reaction mix at 100° C. for 16hr. The reaction mix was then evaporated under vacuum to remove thevolatiles and the crude residue thus obtained was purified by columnchromatography (2-3% EA/Hex) to afford ethyl1-(1-methylcyclohexyl)pyrazole-4-carboxylate 5 (4 g, 13.54 mmol, 28.94%yield, 80% purity) as a yellowish oil; LCMS (ES+)=237.4 [M+H]+.

Step-4: Synthesis of [1-(1-methylcyclohexyl)pyrazol-4-yl]methanol 6: Toa stirred solution of ethyl 1-(1-methylcyclohexyl)pyrazole-4-carboxylate5 (1.4 g, 5.92 mmol) in THF (10.0 mL) was added DIBAL-H (1.6 M, 18.51mL) at −78° C. and stirred at this temp. for 1 h. The reaction mixturewas slowly allowed to come to RT and stirred for 6 h. The progress ofthe reaction was monitored via TLC/LC-MS. The reaction mixture was thenagain cooled to ˜−78° C., quenched with satd. NH4Cl soln., slowlyallowed to come to RT and stirred for some time. The solid residuesettled down, the liquid portion was filtered via celite, and thoroughlywashed with DCM. The organic layer was washed with water, brine anddried over anhyd. Na₂SO₄. Evaporation of the organic layer gave[1-(1-methylcyclohexyl)pyrazol-4-yl]methanol 6 (700 mg, 3.24 mmol,54.74% yield, 90% purity) as a viscous liquid; LCMS (ES+)=195.3 [M+H]+.

Step-5: Synthesis of 1-(1-methylcyclohexyl)pyrazole-4-carbaldehyde 7: Toa stirred solution of [1-(1-methylcyclohexyl)pyrazol-4-yl]methanol 6(1.83 g, 9.42 mmol) in Acetonitrile (50 mL) was added Dioxomanganese(8.19 g, 94.20 mmol) at rt and stirred the reaction mixture for 16 h.The progress of the reaction was monitored via TLC/LC-MS, which showedformation of aldehyde as well as presence of un-reacted SM. The reactionmixture was then filtered via celite, thoroughly washed with EtOAc. andevaporated under vacuum to obtain a crude which was purified by columnchromatography (eluted with 8-9% EA/Hex) to yield1-(1-methylcyclohexyl)pyrazole-4-carbaldehyde 7 (740 mg, 3.46 mmol,36.78% yield, 90% purity) as colorless viscous liquid; LCMS (ES+)=193.2[M+H]+.

Step-6: Synthesis of6-[hydroxy-[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one9: To the stirred solution of1-(1-methylcyclohexyl)pyrazole-4-carbaldehyde 7 (0.5 g, 2.60 mmol) inTHF (25 mL) was added Phenyllithium, typically 1.9 M in di-n-butyl ether(1.8 M, 1.59 mL) at −78° C. and the reaction was stirred at the sametemperature for 30 minutes followed by the addition of Butyllithium,typically 2.5 M in n-Hexane (1.7 M, 1.68 mL) at −78° C. and after theaddition was complete the temperature was allowed to increase to −40° C.and the reaction mixture was stirred at the same temperature for 30minutes followed by the addition of 6-bromo-1H-benzo[cd]indol-2-one 8(645.17 mg, 2.60 mmol) in THF (25 mL) at −78° C. and then the reactionmixture was allowed to warm to room temperature and was continued for 16hours. It was quenched with saturated ammonium chloride solution,extracted with ethyl acetate, washed with water, brine, dried oversodium sulfate and was concentrated under reduced pressure. It waspurified by Comb flash (eluting with 75-80% EA/Hex) to afford6-[hydroxy-[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one9 (220 mg, 547.81 umol, 21.06% yield, 90% purity) as yellowish solid;LCMS (ES+)=362.2 [M+H]+.

Step-7: Synthesis of6-[[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one10: To a stirred solution of6-[hydroxy-[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one9 (125 mg, 345.84 umol) in DCE (5 mL) was added Triethylsilane (160.86mg, 1.38 mmol, 220.96 uL) and Trifluoroacetic acid (315.46 mg, 2.77mmol, 213.15 uL) in a sealed tube. It was heated at 70° C. for 2 h. Theprogress of the reaction was monitored via TLC/LC-MS. The volatiles wereremoved under vacuum to obtain a crude mass which was dissolved in DCM,washed thoroughly with satd. NaHCO₃ soln. and finally dried over anhyd.Na₂SO₄. The solvent was evaporated to furnish the crude desired product6-[[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one10 (105 mg, 273.57 umol, 79.10% yield, 90% purity) as brownish floppysolid. It would be used in the next step without further purification;LCMS (ES+)=346.2 [M+H]+.

Step-8: Synthesis of3-[6-[[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one10 (200 mg, 578.98 umol) in THF (5 mL) was added Sodium hydride (60%dispersion in mineral oil; 221.84 mg, 5.79 mmol, 60% purity) at 0° C.and the reaction mixture was stirred at this temperature for 5 min.Ice-bath was then removed and the reaction mixture was stirred foranother 10 min before 3-bromopiperidine-2,6-dione 11 (555.85 mg, 2.89mmol) was added to it at once and the reaction mixture was stirred atthis temperature for another 10 min. Subsequently, the reaction mixturewas heated at 70° C. for 18 hr. After that reaction was quenched withcold water and extracted with ethyl acetate, dried over sodium sulphate,and concentrated under reduced pressure to give the crude. This crudewas purified by Combi-Flash Column Chromatography (eluting with 60%EA/Hex) to eventually afford the title compound3-[6-[[1-(1-methylcyclohexyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione12 (65 mg, 140.43 umol, 24.25% yield, 98.63% purity) Compound 198 as ayellow solid (obtained after lyophilization). LCMS (ES+)=457.2 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H, D2O Exchangeable), 8.40 (d,J=8.2 Hz, 1H), 8.09 (d, J=6.7 Hz, 1H), 7.85-7.81 (m, 1H), 7.69 (s, 1H),7.35 (d, J=7.2 Hz, 1H), 7.29 (s, 1H), 7.08 (d, J=7.2 Hz, 1H), 5.46-5.41(m, 1H), 4.20 (s, 2H), 2.98-2.90 (m, 1H), 2.79-2.73 (m, 1H), 2.69-2.62(m, 1H), 2.18 (m, 2H), 2.09-2.07 (m, 1H), 1.65-1.63 (m, 2H), 1.46 (m,2H), 1.46 (m, 4H), 1.35 (m, 3H).

Example 105. Synthesis of1-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-piperidyl]methyl]cyclopropanecarbonitrile(Compound 199)

Step-1: Synthesis of1-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-piperidyl]methyl]cyclopropanecarbonitrile:To a stirred solution of3-[2-oxo-6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione1 (300 mg, 676.44 umol) in THF (5 mL) in a sealed tube was addedTriethylamine (136.90 mg, 1.35 mmol, 188.57 uL) and stirred for 5minutes. To it was subsequently added 1-formylcyclopropanecarbonitrile 2(83.63 mg, 879.38 umol) followed by Dibutyltindichloride (246.64 mg,811.73 umol, 181.36 uL) and Phenylsilane (73.20 mg, 676.44 umol, 83.37uL) and the reaction mixture was stirred at 90° C. for 14 h. Thereaction was monitored via TLC and LC. TLC showed the appearance of newspot. The reaction mixture was then diluted with EtOAc, washed withsatd. NaHCO₃ soln. and extracted with EtOAc. The organic layer wasseparated, dried over anhydrous sodium sulphate, and evaporated underreduced pressure to obtain a crude which was subjected to Combi-Flashcolumn chromatography (eluted with 0-5% MeOH/DCM; 2% MeOH/DCM) to yield1-[[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-1-piperidyl]methyl]cyclopropanecarbonitrileCompound 199 (55 mg, 102.80 umol, 15.20% yield, 97.68% purity as ayellowish solid. LCMS (ES+)=523.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ11.13 (s, 1H, D2O Exchangeable), 8.39 (d, J=8.2 Hz, 1H), 8.09 (d, J=6.9Hz, 1H), 7.84 (t, J=7.5 Hz, 1H), 7.61 (s, 1H), 7.36 (d, J=7 Hz, 1H),7.31 (s, 1H), 7.07 (d, J=7.5 Hz, 1H), 5.86 (s, 1H), 5.45-5.43 (m, 1H),4.18 (s, 2H), 4.04 (m, 1H), 3.31 (m, 2H), 3.04-3.01 (m, 2H), 2.95 (m,1H), 2.67 (s, 1H), 2.62 (m, 1H), 2.41 (m, 2H), 2.11 (m, 2H), 1.89 (m,3H), 1.23 (m, 4H).

Example 106. Synthesis of3-[6-[[3-chloro-1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 200)

Step-1: Synthesis of tert-butyl4-(3-amino-4-bromo-pyrazol-1-yl)piperidine-1-carboxylate 3: To a stirredsolution of 4-bromo-1H-pyrazol-3-amine 1 (10 g, 61.73 mmol) in DMF (150mL) was added tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate 2(20.69 g, 74.08 mmol) followed by Cesium carbonate (40.23 g, 123.47mmol) and the reaction mixture was stirred in a seal tube at 90° C. for16 hr. SM was consumed in TLC. The reaction mixture was then dilutedwith ethyl acetate and washed with chilled water followed by brine. Thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to get the crude which was purifiedby column chromatography on silica gel (eluting with 45% ethyl acetatein Hexane to get the desired product tert-butyl4-(3-amino-4-bromo-pyrazol-1-yl)piperidine-1-carboxylate 3 (6 g, 13.90mmol, 22.52% yield, 80% purity) as dark green color semi liquid; LC-MS(ES+)=347.3 [M+H]+.

Step-2: Synthesis of tert-butyl4-(4-bromo-3-chloro-pyrazol-1-yl)piperidine-1-carboxylate 4: To aacetonitrile (20 mL) was added tert-Butyl nitrite, tech. 90% (1.49 g,13.03 mmol, 1.72 mL, 90% purity) followed by CuCl (1.29 g, 13.03 mmol)and the reaction mixture was then slowly heated up to 65° C. At thispoint, tert-butyl4-(3-amino-4-bromo-pyrazol-1-yl)piperidine-1-carboxylate 3 (3 g, 8.69mmol) dissolved in Acetonitrile (10 mL) was slowly added to the reactionmixture. The reaction mixture was stirred at this temperature for 0.5 h.TLC shows a new non polar spot and starting was consumed. Water was thenadded. The reaction mixture was then cooled to room temperature; waterwas added and extracted with EtOAc. The organic part was then washedwith saturated sodium bicarbonate solution and brine solution and thenit was dried over sodium sulfate and the organic part was concentratedunder reduced pressure to afford the crude product. The crude was thenpurified by column chromatography eluting 10% of ethyl acetate in Hexaneto afford tert-butyl4-(4-bromo-3-chloro-pyrazol-1-yl)piperidine-1-carboxylate 4 (1 g, 2.47mmol, 28.40% yield, 90% purity) as a white solid.

Step-3: Synthesis of tert-butyl4-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate6: A stirred solution of tert-butyl4-(4-bromo-3-chloro-pyrazol-1-yl)piperidine-1-carboxylate 4 (2 g, 5.48mmol) and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane5 (2.09 g, 8.23 mmol) in 1,4 dioxane (20 mL) was degassed with argon,and to this soln was sequentially added Potassium Acetate (1.61 g, 16.45mmol, 1.03 mL) and finally Pd(dppf)C12.DCM (447.88 mg, 548.45 umol) andagain degassed for 5 minutes before the reaction mixture was heated at100° C. for 16 h. TLC was checked and LC-MS was analyzed which showedthe desired mass of the Boronate ester derivative. The reaction mixturewas diluted with EtOAc, layers were separated. The organic layer waswashed with water, brine dried over NaSO4 and concentrated under reducedpressure to afford tert-butyl4-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate6 (1.6 g, 1.17 mmol, 21.26% yield, 30% purity) as brown sticky solidwhich was used in next step without further purification; LCMS(ES+)=412.2 [M+H]+.

Step-4: Synthesis of tert-butyl4-[3-chloro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate8: To a stirred solution of6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 7 (2.1g, 4.97 mmol) and tert-butyl4-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate6 (7.68 g, 7.46 mmol) in a sealed tube intoluene (20 mL) was addedTripotassium phosphate (3.69 g, 17.41 mmol). It was degassed with argonfor 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (862.05 mg,746.01 umol) was then added to the reaction mixture, and degassed foranother 5 min. It was then heated at 90° C. for 16 h. The reactionmixture was cooled to RT, diluted with ethyl acetate, filtered overcelite, and concentrated under reduced pressure to get crude mass whichwas purified by Combi-flash Column Chromatography using 35% EtOAc-Hex aseluent to afford tert-butyl4-[3-chloro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate8 (800 mg, 1.09 mmol, 21.92% yield, 80% purity) as yellow viscousliquid; LCMS (ES+)=587.1 [M+H]+.

Step-5: Synthesis of6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo one 9: Totert-butyl4-[3-chloro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate8 (500 mg, 851.63 umol) in Trifluoroacetic acid (10 mL) was addedTrifluoromethanesulfonic Acid (2.56 g, 17.03 mmol, 1.49 mL) at 0° C. Thereaction mixture was allowed to come to RT and stirred for 16 hr at sametemp. After complete consumption of SM, reaction mixture was evaporatedto remove the excess reagents. It was dissolved in DCM, and washed withsatd. NaHCO₃. Organic portion was separated, dried over sodium sulfateand concentrated under reduced pressure to furnish the desired product6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one9 (200 mg, 381.63 umol, 44.81% yield, 70% purity) as brown viscousliquid, which was used in the next step without further purification;LCMS (ES+)=367.1 [M+H]+.

Step-6: Synthesis of tert-butyl4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate10: To a stirred solution of6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one9 (300 mg, 817.79 umol) in DCM (10 mL) was added Triethylamine (248.26mg, 2.45 mmol, 341.95 uL) at 0° C. followed by Triethylamine (248.26 mg,2.45 mmol, 341.95 uL) and the reaction was stirred at room temperaturefor 16 hours. TLC was checked which showed complete consumption of thestarting material along with the formation of the desired spot. Thereaction mixture was diluted with ethyl acetate, washed with water andthe organic fraction was separated. It was dried over anhydrous sodiumsulphate and evaporated under reduced pressure to obtain the crudecompound which was purified by flash chromatography using 70-75% EA-Hexto afford tert-butyl4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate10 (160 mg, 308.38 umol, 37.71% yield, 90% purity) as brown solid; LCMS(ES+)=467.1 [M+H]+.

Step-7: Synthesis of tert-butyl4-[3-chloro-4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate12: To a stirred solution of tert-butyl4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate10 (220 mg, 471.13 umol) in THF (5 mL), was added Sodium hydride (376.87mg, 9.42 mmol, 60% purity) at 0° C. portion wise and the reactionmixture was stirred at this temperature for 3-5 min. Ice-bath was thenremoved and the reaction mixture was stirred for another 3-5 min before3-bromopiperidine-2,6-dione 11 (452.31 mg, 2.36 mmol) was added to it at0° C. portion wise and the reaction mixture was stirred at thistemperature for another 1-2 min. Subsequently, the reaction mixture washeated at 70° C. for 1 hr. After that reaction was quenched with ice andcold water and extracted with ethyl acetate, dried over sodium sulphate,and concentrated under reduced pressure to give the crude. This crudewas purified by repetitive washing with Diethyl ether to eventuallyafford the title compound tert-butyl4-[3-chloro-4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate12 (180 mg, 280.25 umol, 59.48% yield, 90% purity) as yellow solid(obtained after lyophilization); LCMS (ES+)=578.3 [M+H]+.

Step-8: Synthesis of3-[6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione;hydrochloride 13: To a stirred solution of tert-butyl4-[3-chloro-4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate12 (170.00 mg, 294.09 umol) in Dioxane (10 mL) was added Dioxane-HCl (4M, 1.47 mL) drop wise at 0° C. It was then allowed to come to RT andstirred for 16 h. Crude LCMS showed complete consumption of startingmaterial and formation of product. The reaction mass was evaporated todryness eventually to afford3-[6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione;hydrochloride 13 (100 mg, 184.68 umol, 62.80% yield, 95% purity) asyellowish solid; LCMS (ES+)=478.3 [M+H]+.

Step-9: Synthesis of3-[6-[[3-chloro-1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of3-[6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione13 (as HCl salt; 150 mg, 313.85 umol) in THF (6 mL) in a sealed tube wasadded Triethylamine (79.40 mg, 784.61 umol, 109.36 uL) and stirred for 5minutes. To it was subsequently added 1-methylcyclobutanecarbaldehyde 14(36.96 mg, 376.61 umol, 36.24 uL) followed by Dibutyltindichloride(114.43 mg, 376.61 umol, 84.14 uL) and Phenylsilane (33.96 mg, 313.85umol, 38.68 uL) and the reaction mixture was stirred at 90° C. for 14 h.The reaction was monitored via TLC and LC. TLC showed the appearance ofnew spot. The reaction mixture was then diluted with EtOAc, washed withsatd. NaHCO₃ soln. and extracted with EtOAc. The organic layer wasseparated, dried over anhydrous sodium sulphate, and evaporated underreduced pressure to obtain a crude which was subjected to Combi-Flashcolumn chromatography (eluted with 0-5% MeOH/DCM; 2% MeOH/DCM) to yield3-[6-[[3-chloro-1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 200 (65 mg, 109.50 umol, 34.89% yield, 94.35% purity as a lightyellow solid; LCMS (ES+)=560.2 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ11.12 (s, 1H, D2O Exchangeable), 8.38 (d, J=8.2 Hz, 1H), 8.10 (d, J=7Hz, 1H), 7.85 (t, J=7.8 Hz, 1H), 7.69 (s, 1H), 7.30 (d, J=7.4 Hz, 1H),7.07 (d, J=7.4 Hz, 1H), 5.43 (dd, J=5.1, 12.8 Hz, 1H), 4.13 (s, 2H),3.99 (m, 1H), 2.95 (m, 1H), 2.75-2.50 (m, 4H), 2.22 (m, 2H), 2.09-1.99(m, 3H), 1.93-1.89 (m, 1H), 1.82-1.74 (m, 5H), 1.72-1.69 (m, 1H),1.61-1.56 (m, 3H), 1.13 (s, 3H).

Example 107. Synthesis of tert-butyl4-[(4-ethoxycarbonylphenyl)methylene]piperidine-1-carboxylate (Compound201)

Step-1: Synthesis of tert-butyl4-[(4-ethoxycarbonylphenyl)methylene]piperidine-1-carboxylate: To astirred solution of3-[6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione1 (as HCl salt; 150 mg, 313.85 umol) in THF (5 mL) in a sealed tube wasadded Triethylamine (79.40 mg, 784.61 umol, 109.36 uL) and stirred for 5minutes. To it was subsequently added1-(trifluoromethyl)cyclopropanecarbaldehyde 2 (65.01 mg, 470.77 umol,35.56 uL) followed by Dibutyltindichloride (114.43 mg, 376.61 umol,84.14 uL) and Phenylsilane (40.75 mg, 376.61 umol, 46.42 uL) and thereaction mixture was stirred at 90° C. for 14 h. The reaction wasmonitored via TLC and LC. TLC showed the appearance of new spot. Thereaction mixture was then diluted with EtOAc, washed with satd. NaHCO₃soln. and extracted with EtOAc. The organic layer was separated, driedover anhydrous sodium sulphate, and evaporated under reduced pressure toobtain a crude which was subjected to Combi-Flash column chromatography(eluted with 0-5% MeOH/DCM; 0.5% MeOH/DCM) to yield3-[6-[[3-chloro-1-[1-[[1-(trifluoromethyl)cyclopropyl]methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 201 (57 mg, 90.69 umol, 28.90% yield, 95.47% purity as alight-yellow solid. LCMS (ES+)=600.5 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6):δ 11.12 (s, 1H, D2O Exchangeable), 8.37 (d, J=8.2 Hz, 1H), 8.10 (d,J=6.9 Hz, 1H), 7.85 (t, J=7.6 Hz, 1H), 7.69 (s, 1H), 7.30 (d, J=7.6 Hz,1H), 7.08 (d, J=7.2 Hz, 1H), 5.45-5.43 (m, 1H), 4.13 (s, 2H), 4.04-4.02(m, 1H), 2.95-2.92 (m, 3H), 2.67-2.72 (s, 1H), 2.67-2.62 (m, 1H), 2.49(m, 2H), 2.09-2.08 (m, 1H), 2.04-1.98 (m, 2H), 1.85-1.81 (m, 4H), 0.94(m, 2H), 0.71 (m, 2H).

Example 108. Synthesis of3-[6-[[4-[[4-(4-fluorophenyl)sulfonylpiperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzoindol-1-yl]piperidine-2,6-dione(Compound 202)

Step-1: Synthesis of1-[[4-(chloromethyl)phenyl]methyl]-4-(4-fluorophenyl)sulfonyl-piperazine3: To a stirred solution of 1-(4-fluorophenyl)sulfonylpiperazine 2 (1.00g, 4.11 mmol, 1.00 mL) in Acetone (15 mL) was added Potassium carbonate,anhydrous, 99% (568.07 mg, 4.11 mmol, 248.07 uL) and stirred at 50° C.for 20 minutes. Subsequently to it was added1,4-bis(chloromethyl)benzene 1 (719.51 mg, 4.11 mmol, 506.70 uL) and thereaction mixture was heated for another 6 h. The reaction mixture wascooled to RT, evaporated to remove the volatiles, water was added andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over sodium sulphate, and concentrated under reducedpressure to give the crude. This crude was purified by Combi-Flashcolumn chromatography to afford1-[[4-(chloromethyl)phenyl]methyl]-4-(4-fluorophenyl)sulfonyl-piperazine3 (700 mg, 1.74 mmol, 42.26% yield, 95% purity) as a viscous liquid.

Step-2: Synthesis of6-[[4-[[4-(4-fluorophenyl)sulfonylpiperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one5: To a stirred solution of1-[[4-(chloromethyl)phenyl]methyl]-4-(4-fluorophenyl)sulfonyl-piperazine3 (700 mg, 1.83 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one4 (1.08 g, 3.66 mmol) in ethanol (5 mL) and Toluene (10 mL) was addedPotassium phosphate tribasic anhydrous (1.16 g, 5.48 mmol) and thereaction mass was degassed under nitrogen atmosphere over 5 minutes.Then Tri-o-Tolyl phosphine (111.29 mg, 365.65 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (167.42 mg, 182.83umol) were added to this reaction mass, and degassed for another 5 min.It was then heated at 90° C. for 16 h. The reaction mixture was cooledto RT, diluted with ethyl acetate, filtered over celite, andconcentrated under reduced pressure to get crude mass which was purifiedby Combi-flash Column Chromatography using 20% EtOAc-Hex as eluent toafford6-[[4-[[4-(4-fluorophenyl)sulfonylpiperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one5 (450 mg, 829.14 umol, 45.35% yield, 95% purity) as yellow solid; LCMS(ES+)=516.3 [M+H]+.

Step-3: Synthesis3-[6-[[4-[[4-(4-fluorophenyl)sulfonylpiperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[4-[[4-(4-fluorophenyl)sulfonylpiperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one5 (100 mg, 193.95 umol) in THF (10 mL), was added Sodium hydride (168.15mg, 4.20 mmol, 60% purity) at 0° C. portion wise and the reactionmixture was stirred at this temperature for 3-5 min. Ice-bath was thenremoved and the reaction mixture was stirred for another 3-5 min before3-bromopiperidine-2,6-dione (186.20 mg, 969.75 umol) was added to it at0° C. portion wise and the reaction mixture was stirred at thistemperature for another 1-2 min. Subsequently, the reaction mixture washeated at 70° C. for 1 hr. After that reaction was quenched with ice andcold water and extracted with ethyl acetate, dried over sodium sulphate,and concentrated under reduced pressure to give the crude. This crudewas purified by Combi-flash Column Chromatography to afford the titlecompound3-[6-[[4-[[4-(4-fluorophenyl)sulfonylpiperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 202 (65 mg, 94.11 umol, 48.53% yield, 90.74% purity as yellowsolid (obtained after lyophilization); LCMS (ES+)=627.6 [M+H]+. 1H NMR(400 MHz, DMSO-d6): δ 11.09 (s, 1H, D2O Exchangeable), 8.28 (d, J=8.3Hz, 1H), 8.04 (d, J=7.0 Hz, 1H), 7.79-7.73 (m, 3H), 7.45 (t, J=7.7 Hz,2H), 7.36 (d, J=7.4 Hz, 1H), 7.19-7.17 (m, 2H), 7.10-7.06 (m, 3H),5.44-5.39 (m, 1H), 4.33 (s, 2H), 3.36 (s, 2H), 2.95-2.89 (m, 1H), 2.83(m, 4H), 2.75-2.71 (m, 1H), 2.67-2.60 (m, 1H), 2.34 (m, 4H), 2.08-2.05(m, 1H).

Example 109. Synthesis of3-[6-[[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 203)

Step-1: Synthesis of tert-butyl4-[(4-ethoxycarbonylphenyl)methylene]piperidine-1-carboxylate 3: To astirred solution of ethyl 4-iodoethylbenzoate 1 (5 g, 21.39 mmol, 3.57mL) in DMF (15 mL) in a sealed tube was added tert-butyl4-methylenepiperidine-1-carboxylate 2 (12.66 g, 64.17 mmol) andresulting solution was degassed with argon for 5 minutes followed theaddition of Triethyl amine (10.82 g, 106.95 mmol, 14.91 mL) andcyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(1.75 g, 2.14 mmol). It was heated at 100° C. for 16 h. After completeconsumption of SM as evidenced from TLC (20% ethyl acetate in hexane),RM was filtered through celite bed, washed with EtOAc and ice cooledwater was added to the filtrate. Aqueous part was extracted with ethylacetate. The organic layer was washed with water, brine and dried overNaSO4 and concentrated under reduced pressure to afford a crude whichwas purified by Combi-flash Column Chromatography (eluting at 5% ethylacetate in hexane) to afford mixture of isomers of tert-butyl4-[(4-ethoxycarbonylphenyl)methylene]piperidine-1-carboxylate 3 (4 g,10.42 mmol, 48.72% yield, 90% purity) as colorless gum.

Step-2: Synthesis of tert-butyl4-[(4-ethoxycarbonylphenyl)methyl]piperidine-1-carboxylate 4: To astirred soln of tert-butyl4-[(4-ethoxycarbonylphenyl)methylene]piperidine-1-carboxylate 3 (2 g,5.79 mmol) in EtOAc (100 mL) was added Pd-Charcoal (2 g). A H2 balloonwas attached to it, and hydrogenated applying vacuum. It was thenstirred at RT. After the reaction was over, it was filtered over Celite,evaporated and the crude mass was subjected to Combiflash chromatographyover silica to obtain the pure tert-butyl4-[(4-ethoxycarbonylphenyl)methyl]piperidine-1-carboxylate 4 (1.5 g,4.10 mmol, 70.84% yield, 95% purity) as colorless viscous liquid; LCMS(ES+)=348.4 [M+H]+.

Step-3: Synthesis ethyl 4-(4-piperidylmethyl)benzoate; hydrochloride 5:To a stirred solution of tert-butyl4-[(4-ethoxycarbonylphenyl)methyl]piperidine-1-carboxylate 4 (4 g, 11.51mmol) in Dioxane (20 mL) was added Dioxane-HCl (4 M, 57.56 mL) drop wiseat 0° C. It was then allowed to come to RT and stirred for 16 h. CrudeLCMS showed complete consumption of starting material and formation ofproduct. The reaction mass was evaporated to dryness eventually toafford ethyl 4-(4-piperidylmethyl)benzoate; hydrochloride 5 (4 g, 9.09mmol, 78.99% yield, 95% purity) as a colorless solid; LCMS (ES+)=248.2[M+H]+.

Step-4: Synthesis of ethyl4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]benzoate 7: To a stirredsolution of ethyl 4-(4-piperidylmethyl)benzoate; hydrochloride 5 (2 g,7.05 mmol) in tert-Butanol (40 mL) was added Caesium carbonate (9.18 g,28.19 mmol) under argon in a sealed tube and degassed for 10 minutes. Itwas stirred for another 20 min under this condition.1-fluoro-4-iodo-benzene 6 (4.69 g, 21.14 mmol, 2.43 mL) was then addedand was degassed with argon for 5 minutes. Subsequently RuPhos (328.85mg, 704.74 umol) was added to the reaction mixture followed byTris(dibenzylideneacetone)dipalladium(0) (214.50 mg, 704.74 umol), anddegassed for another 5 min. It was then heated at 90° C. for 16 h. Thereaction mixture was cooled to RT, diluted with ethyl acetate, washedwith satd. NaHCO₃ soln, and extracted with Ethyl acetate. The organiclayer was washed with water, brine and dried over NaSO4 and concentratedunder reduced pressure to afford a crude which was purified byCombi-flash Column Chromatography using 3.5% EtOAc-Hex as eluent toobtain ethyl 4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]benzoate 7 (550mg, 1.53 mmol, 21.72% yield, 95% purity) as a brown sticky liquid; LCMS(ES+)=341.9 [M+H]+.

Step-5: Synthesis of[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methanol 8: To astirred solution of ethyl4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]benzoate 7 (1.3 g, 3.81 mmol)in THF (5.0 mL) was added DIBAL-H (1.6 M, 9.52 mL) at −78° C. andstirred within the temperature range of −78-−50° C. for 2 h. Theprogress of the reaction was monitored via TLC. After completion of SM(4 h), the reaction mixture was then quenched with satd. Rochelle saltsoln., slowly allowed to come to RT and stirred for some time. The solidresidue settled down, the liquid portion was filtered via celite, andthoroughly washed with DCM. The organic layer was washed with water,brine and dried over anhyd. Na₂SO₄. and concentrated under reducedpressure to afford a crude which was purified by Combi-flash ColumnChromatography using 20% EtOAc-Hex as eluent to obtain[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methanol 8 (700 mg,2.22 mmol, 58.34% yield, 95% purity) as a white solid. LCMS (ES+)=300.3[M+H]+.

Step-6: Synthesis of4-[[4-(chloromethyl)phenyl]methyl]-1-(4-fluorophenyl)piperidine 9: To astirred suspension of[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methanol 8 (450 mg,1.50 mmol) in DCM (10 mL) was added Triethylamine (760.49 mg, 7.52 mmol,1.05 mL) at 0° C. and stirred under cold condition for 30 minutes.Subsequently, Mesyl chloride (688.73 mg, 6.01 mmol, 465.36 uL) was addeddrop wise at 0° C. and the reaction mixture was allowed to come to RTand stirred at that temperature for 16 h. The volatiles were removed toobtain a crude mass which was dissolved in DCM, washed thoroughly withsatd. NaHCO3 soln. and finally dried over anhyd. Na₂SO₄. The solvent wasevaporated to furnish the desired product4-[[4-(chloromethyl)phenyl]methyl]-1-(4-fluorophenyl)piperidine 9 (250mg, 471.95 umol, 31.40% yield, 60% purity) as a viscous liquid (crude).On scratching with diethyl ether and pentane, the product solidified;LCMS (ES+)=318.2 [M+H]+.

Step-7: Synthesis of6-[[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one11: To a stirred solution of4-[[4-(chloromethyl)phenyl]methyl]-1-(4-fluorophenyl)piperidine 9 (450mg, 1.42 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one10 (626.82 mg, 2.12 mmol) in Ethanol (5 mL) and Toluene (10 mL) wasadded Potassium phosphate tribasic anhydrous (901.64 mg, 4.25 mmol) andthe reaction mass was degassed under nitrogen atmosphere over 5 minutes.Then Tri-o-Tolyl phosphine (86.19 mg, 283.17 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (129.65 mg, 141.59umol) were added to this reaction mass, and degassed for another 5 min.It was then heated at 90° C. for 16 h. The reaction mixture was cooledto RT, diluted with ethyl acetate, filtered over celite, and thoroughlywith Ethyl acetate. The organic layer was washed with water, brine anddried over NaSO4 and concentrated under reduced pressure to afford acrude which was purified by Combi-flash Column Chromatography using18-20% EtOAc-Hex as eluent to obtain6-[[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one11 (200 mg, 399.52 umol, 28.22% yield, 90% purity) as a yellow solid;LCMS (ES+)=451.1 [M+H]+.

Step-8: Synthesis of3-[6-[[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one11 (350 mg, 776.84 umol) in THF (10 mL), was added Sodium hydride(621.41 mg, 15.54 mmol, 60% purity) at 0° C. portion wise and thereaction mixture was stirred at this temperature for 3-5 min. Ice-bathwas then removed and the reaction mixture was stirred for another 3-5min before 3-bromopiperidine-2,6-dione 12 (745.80 mg, 3.88 mmol) wasadded to it at 0° C. portion wise and the reaction mixture was stirredat this temperature for another 1-2 min. Subsequently, the reactionmixture was heated at 70° C. for 1 hr. After that reaction was quenchedwith ice and cold water and extracted with ethyl acetate, dried oversodium sulphate, and concentrated under reduced pressure to give a crudewhich was purified by Combi-flash Column Chromatography using 40%EtOAc-Hex as eluent to obtain3-[6-[[4-[[1-(4-fluorophenyl)-4-piperidyl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 203 (90 mg, 104.69 umol, 13.48% yield, 98% purity as yellowsolid (obtained after lyophilization); LCMS (ES+)=562.5 [M+H]+. 1H NMR(400 MHz, DMSO-d6): δ 11.12 (s, 1H, D2O Exchangeable), 8.33 (d, J=8.3Hz, 1H), 8.07 (d, J=6.9 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.39 (d, J=7.3Hz, 1H), 7.20 (d, J=7.8 Hz, 2H), 7.11-7.07 (m, 3H), 6.98 (t, J=8.8 Hz,2H), 6.89-6.87 (m, 2H), 5.46-5.42 (m, 1H), 4.36 (s, 2H), 3.52 (d, J=12.0Hz, 2H), 2.95-2.91 (m, 1H), 2.78-2.73 (m, 1H), 2.67-2.63 (m, 1H),2.49-2.46 (m, 3H), 2.10-2.07 (m, 1H), 1.61-1.58 (m, 3H), 1.28-1.23 (m,3H).

Example 110. Synthesis of3-[6-[[1-[1-[1-[(dimethylamino)methyl]cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 204) and3-[6-[[1-[1-[1-(hydroxymethyl)cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 205)

Step-1: Synthesis of methyl1-[(dimethylamino)methyl]cyclobutanecarboxylate 2: To a stirred solutionof methyl 1-formylcyclobutanecarboxylate 1 (100 mg, 703.47 umol) in THF(5 mL) in a sealed tube was added Triethylamine (177.96 mg, 1.76 mmol,245.13 uL) and stirred for 5 minutes. To it was subsequently addedN-methylmethanamine; hydrochloride (86.05 mg, 1.06 mmol) followed byDibutyltindichloride (256.50 mg, 844.17 umol, 188.60 uL) andPhenylsilane (91.35 mg, 844.17 umol, 104.04 uL) and the reaction mixturewas stirred at 90° C. for 14 h. The reaction mixture was then dilutedwith EtOAc, washed with satd. NaHCO₃soln. and extracted with EtOAc. Theorganic layer was separated, dried over anhydrous sodium sulphate, andevaporated under reduced pressure to obtain methyl1-[(dimethylamino)methyl]cyclobutanecarboxylate 2 (40 mg, 116.80 umol,16.60% yield, 50% purity) (crude). [NMR and GC-MS support theformation].

Step-2: Synthesis of 1-[(dimethylamino)methyl]cyclobutanecarboxylic acid3: To a stirred solution of methyl1-[(dimethylamino)methyl]cyclobutanecarboxylate 2 (100.00 mg, 116.80umol) in THF (2.5 mL) was added LiOH.H2O (5.88 mg, 140.16 umol, 247.34uL) at 0° C. and the reaction mixture was allowed to come to RT andcontinued stirring at RT for 16 h. The reaction mixture was evaporatedto obtain a crude mass which was acidified with HCl in Dioxane (4 Mstock solution) to pH 1. The combined reaction mass was then lyophilized(using CH3CN/Water mixture) to obtain1-[(dimethylamino)methyl]cyclobutanecarboxylic acid 3 (60 mg, 76.33umol, 65.35% yield, 20% purity) as colorless solid, used for the nextstep without further purification. N.B. Aqueous work-up could not beperformed as the desired acid compound was found to have the tendency tomix up with the aqueous portion, hence the obtained mass consists of thedesired 1-[(dimethylamino)methyl]cyclobutanecarboxylic acid 3 (60 mg,76.33 umol, 65.35% yield, 20% purity) along with NaCl. It was planned tobe utilized in the next step without further purification.

Step-3: Synthesis3-[6-[[1-[1-[1-[(dimethylamino)methyl]cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of3-[2-oxo-6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione;hydrochloride 4 (30.53 mg, 63.61 umol) was added DIPEA (32.88 mg, 254.44umol, 44.32 uL) followed by1-[(dimethylamino)methyl]cyclobutanecarboxylic acid 3 (60 mg, 76.33umol) and HATU (36.28 mg, 95.41 umol) and reaction mixture was stirredat 25° C. for 16 hr. The progress of the reaction was monitored via TLCand LC-MS. Water was then added to the reaction mixture, and the aqueouslayer was extracted with EtOAc. The organic layers were combined, driedover anhyd. Na₂SO₄, and filtered, and the solvents were removed underreduced pressure to give a residue, which was purified by columnchromatography (eluted with 3% MeOH/DCM) to yield a mixture of products.It was further repurified in PREP-HPLC eventually to obtain3-[6-[[1-[1-[1-[(dimethylamino)methyl]cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 204 (3 mg, 9.78 umol, 15.38% yield, 95% purity) as a yellowsolid (after lyophilization). LCMS (ES+)=583.7 [M+H]+. Apart from this,one by-product 5a was also formed, probably, while attempting to preparethe actual starting material 3 (via 2), presumably it was not formed, orformed in traces, rather 3a (via 2a) was formed which eventually gavethe undesired coupled product3-[6-[[1-[1-[1-(hydroxymethyl)cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 205 (12 mg, 20.81 umol, 19.63% yield, 96.35% purity) as ayellow solid. LCMS (ES+)=556.6 [M+H]+.

Example 111. Synthesis of3-[6-[[5-chloro-2-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-3-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 206)

Step-1: Synthesis of tert-butyl4-(3-amino-4-bromo-pyrazol-1-yl)piperidine-1-carboxylate 3: To a stirredsolution of 4-bromo-1H-pyrazol-3-amine 1 (10 g, 61.73 mmol) in DMF (150mL) was added tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate 2(20.69 g, 74.08 mmol) followed by Cesium carbonate (40.23 g, 123.47mmol) and the reaction mixture was stirred in a seal tube at 90° C. for16 hr. SM was consumed in TLC. The reaction mixture was then dilutedwith ethyl acetate and washed with chilled water followed by brine. Thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to get the crude which was purifiedby column chromatography on silica gel (eluting with 45% ethyl acetatein Hexane to get the desired product tert-butyl4-(3-amino-4-bromo-pyrazol-1-yl)piperidine-1-carboxylate 3 (6 g, 13.90mmol, 22.52% yield, 80% purity) as dark green color semi liquid. LC-MS(ES+)=347.3 [M+H]+.

Step-2: Synthesis of tert-butyl4-(4-bromo-3-chloro-pyrazol-1-yl)piperidine-1-carboxylate 4: To aacetonitrile (20 mL) was added tert-Butyl nitrite, tech. 90% (1.49 g,13.03 mmol, 1.72 mL, 90% purity) followed by CuCl (1.29 g, 13.03 mmol)and the reaction mixture was then slowly heated up to 65° C. At thispoint, tert-butyl4-(3-amino-4-bromo-pyrazol-1-yl)piperidine-1-carboxylate 3 (3 g, 8.69mmol) dissolved in Acetonitrile (10 mL) was slowly added to the reactionmixture. The reaction mixture was stirred at this temperature for 0.5 h.TLC shows a new non polar spot and starting was consumed. Water was thenadded. The reaction mixture was then cooled to room temperature; waterwas added and extracted with EtOAc. The organic part was then washedwith saturated sodium bicarbonate solution and brine solution and thenit was dried over sodium sulfate and the organic part was concentratedunder reduced pressure to afford the crude product. The crude was thenpurified by column chromatography eluting 10% of ethyl acetate in Hexaneto afford tert-butyl4-(4-bromo-3-chloro-pyrazol-1-yl)piperidine-1-carboxylate 4 (1 g, 2.47mmol, 28.40% yield, 90% purity) as a white solid.

Step-3: Synthesis of[2-(1-tert-butoxycarbonyl-4-piperidyl)-5-chloro-pyrazol-3-yl]boronicacid 6: To a stirred solution in tert-butyl4-(4-bromo-3-chloro-pyrazol-1-yl)piperidine-1-carboxylate 4 (2 g, 5.48mmol) in dry THF (7 mL) under inert atmosphere at −78° C. was addedn-Butyllithium (1.6 M, 3.43 mL) in a drop-wise fashion. After completionof addition the reaction mixture was stirred for 1 h at sametemperature, and checked TLC. As some SM seemed to be present along withdesired corresponding des-Bromo variant, additional 0.5 mL ofButyllithium was added. After 30 min, trimethyl borate 5 (854.86 mg,8.23 mmol, 934.27 uL) was added drop wise to the reaction mixture, andstirred for 2 hr without adding further dry ice (thereby allowing thereaction temperature to gradually increase). After another 1 h, TLC waschecked and LC-MS was analyzed which showed the desired mass of theBoronic acid derivative. The reaction mixture was quenched with sat.solution of NH4Cl and diluted with EtOAc, layers were separated. Theorganic layer was washed with water, brine dried over NaSO4 andconcentrated under reduced pressure to afford[2-(1-tert-butoxycarbonyl-4-piperidyl)-5-chloro-pyrazol-3-yl]boronicacid 6 (1.4 g, 3.40 mmol, 61.96% yield, 80% purity) as brown stickysolid which was used in next step without further purification; LCMS(ES+)=330.3 [M+H]+.

Step-4: Synthesis of tert-butyl4-[3-chloro-5-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate8: To a stirred solution of6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 7 (1.23g, 3.64 mmol) and[2-(1-tert-butoxycarbonyl-4-piperidyl)-5-chloro-pyrazol-3-yl]boronicacid 6 (1.80 g, 4.37 mmol) in a sealed tube intoluene (6 mL) and Ethanol(3 mL) and 5 drops of water were added tripotassium phosphate (1.93 g,9.10 mmol). It was degassed with argon for 10 minutes.tris-o-tolylphosphane (221.64 mg, 728.18 umol) and Pd2dba3 (333.41 mg,364.09 umol) were then added to the reaction mixture, and degassed foranother 5 min. It was then heated at 90° C. for 16 h. The reactionmixture was cooled to RT, diluted with ethyl acetate, filtered overcelite, washed with EtOAc and concentrated under reduced pressure to getcrude mass which was purified by Combi-flash Column Chromatography using35% EtOAc-Hex as eluent to afford tert-butyl4-[3-chloro-5-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate8 (750 mg, 1.15 mmol, 31.58% yield, 90% purity) as yellow solid; LCMS(ES+)=587.2 [M+H]+.

Step-5: Synthesis of6-[[5-chloro-2-(4-piperidyl)pyrazol-3-yl]methyl]-1H-benzo one 9: Totert-butyl4-[3-chloro-5-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate8 (460.00 mg, 783.50 umol) in Trifluoroacetic acid (10 mL) was addedTrifluoromethanesulfonic Acid (2.35 g, 15.67 mmol, 1.38 mL) at 0° C. Thereaction mixture was allowed to come to RT and stirred for 16 hr at sametemp. After complete consumption of SM, reaction mixture was evaporatedto remove the excess reagents. It was dissolved in DCM, and washed withsatd. NaHCO₃. Organic portion was separated, dried over sodium sulfateand concentrated under reduced pressure to furnish the desired product6-[[5-chloro-2-(4-piperidyl)pyrazol-3-yl]methyl]-1H-benzo[cd]indol-2-one9 (300 mg, 654.23 umol, 83.50% yield, 80% purity) as brown viscousliquid, which was used in the next step without further purification;LCMS (ES+)=367.1 [M+H]+.

Step-6: Synthesis of tert-butyl4-[3-chloro-5-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate10: To a stirred solution of6-[[5-chloro-2-(4-piperidyl)pyrazol-3-yl]methyl]-1H-benzo[cd]indol-2-one9 (550 mg, 1.50 mmol) in DCM (10 mL) was added Triethylamine (455.14 mg,4.50 mmol, 626.91 uL) at 0° C. followed by Di-tert-butyl dicarbonate(392.66 mg, 1.80 mmol, 412.89 uL) and the reaction was stirred at roomtemperature for 6 hours. TLC was checked which showed completeconsumption of the starting material along with the formation of thedesired spot. The reaction mixture was diluted with ethyl acetate,washed with water and the organic fraction was separated. It was driedover anhydrous sodium sulphate and evaporated under reduced pressure toobtain the crude compound which was purified by flash chromatographyusing 70-75% EA-Hex to afford tert-butyl4-[3-chloro-5-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate10 (350 mg, 674.58 umol, 44.99% yield, 90% purity) as brown solid; LCMS(ES+)=467.2 [M+H]+.

Step-7: Synthesis of tert-butyl4-[3-chloro-5-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate12: To a stirred solution of tert-butyl4-[3-chloro-5-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate10 (320.00 mg, 685.29 umol) in THF (5 mL), was added Sodium hydride(548.18 mg, 13.71 mmol, 60% purity) at 0° C. portion wise and thereaction mixture was stirred at this temperature for 3-5 min. Ice-bathwas then removed and the reaction mixture was stirred for another 3-5min before 3-bromopiperidine-2,6-dione 11 (657.91 mg, 3.43 mmol) wasadded to it at at 0° C. portion wise and the reaction mixture wasstirred at this temperature for another 1-2 min. Subsequently, thereaction mixture was heated at 70° C. for 1 hr. After that reaction wasquenched with ice and cold water and extracted with ethyl acetate, driedover sodium sulphate, and concentrated under reduced pressure to givethe crude. This crude was purified by repetitive washing with Diethylether to eventually afford the title compound tert-butyl4-[3-chloro-5-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate12 (350 mg, 544.93 umol, 79.52% yield, 90% purity) as yellow solid(obtained after lyophilization); LCMS (ES+)=578.2 [M+H]+.

Step-8: Synthesis of3-[6-[[5-chloro-2-(1-chloro-4-piperidyl)pyrazol-3-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione;hydrochloride 13: To a stirred solution of tert-butyl4-[3-chloro-5-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate12 (350.00 mg, 605.48 umol) in Dioxane (10 mL) was added Dioxane-HCl (4M, 3.03 mL) drop wise at 0° C. It was then allowed to come to RT andstirred for 16 h. Crude LCMS showed complete consumption of startingmaterial and formation of product. The reaction mass was evaporated todryness eventually to afford3-[6-[[5-chloro-2-(1-chloro-4-piperidyl)pyrazol-3-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione;hydrochloride 13 (200 mg, 349.92 umol, 57.79% yield, 90% purity) asyellowish solid; LCMS (ES+)=478.2 [M+H]+.

Step-9: Synthesis of3-[6-[[5-chloro-2-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-3-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of3-[6-[[5-chloro-2-(4-piperidyl)pyrazol-3-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione13 (as HCl salt; 250 mg, 523.08 umol) in THF (8 mL) in a sealed tube wasadded Triethylamine (105.86 mg, 1.05 mmol, 145.81 uL) and stirred for 5minutes. To it was subsequently added 1-methylcyclobutanecarbaldehyde 14(61.60 mg, 627.69 umol) followed by Dibutyltindichloride (190.72 mg,627.69 umol, 140.24 uL) and Phenylsilane (56.60 mg, 523.08 umol, 64.47uL) and the reaction mixture was stirred at 90° C. for 14 h. Thereaction was monitored via TLC and LC. TLC showed the appearance of newspot. The reaction mixture was then diluted with EtOAc, washed withsatd. NaHCO₃soln. and extracted with EtOAc. The organic layer wasseparated, dried over anhydrous sodium sulphate, and evaporated underreduced pressure to obtain a crude which was subjected to Combi-Flashcolumn chromatography (eluted with 0-5% DCM/MeOH) to yield3-[6-[[5-chloro-2-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-3-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 206 (70 mg, 118.98 umol, 22.75% yield, 95.2% purity as a lightyellow solid; LCMS (ES+)=560.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ11.13 (s, 1H, D2O Exchangeable), 8.36 (d, J=8.3 Hz, 1H), 8.12 (d, J=7Hz, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.31 (d, J=7.4 Hz, 1H), 7.11 (d, J=7.3Hz, 1H), 5.86 (s, 1H), 5.45 (dd, J=5.1, 12.8 Hz, 1H), 4.51 (s, 2H), 4.22(m, 1H), 2.95 (m, 1H), 2.72-2.63 (m, 4H), 2.22 (s, 2H), 2.11-2.02 (m,1H), 1.99-1.84 (m, 5H), 1.89-1.82 (m, 2H), 1.79-1.78 (m, 1H), 1.75-1.70(m, 4H), 1.14 (s, 3H).

Example 112. Synthesis of3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)oxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 207)

Step-1: Synthesis of 4-(4-Formyl-pyrazol-1-yl)-piperidine-1-carboxylicacid tert-butyl ester: To a solution of 1H-pyrazole-4-carbaldehyde (4.7g, 48.91 mmol) and tert-butyl4-methoxysulfonyloxy-piperidine-1-carboxylate (17.34 g, 58.70 mmol) inDMF (50 mL) was added cesium carbonate (39.84 g, 122.28 mmol) and heatedto 90° C. in a sealed tube for 16 h. Crude LCMS showed formation ofproduct. The reaction mass was cooled and added to water. The organicswas extracted with EtOAc. Combined organics was washed with water, brineand dried over Na₂SO₄. Combined solvents was evaporated to dryness andpurified by combiflash with eluting solvent 20-80% EtOAc in hexane toafford tert-butyl 4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate (4 g,11.46 mmol, 23.42% yield, 80% purity) as brown solid; LCMS (ES+)=280.4[M+H]+.

Step-2: Synthesis of(E)-3-(dimethylamino)-2-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)oxy)acrylaldehyde:Phosphorous oxychloride (3.64 g, 23.73 mmol, 2.22 mL) was added indimethyl formamide (1.73 g, 23.73 mmol, 1.84 mL) at 0° C. and stirredfor 15 mins. Compound6-(2,2-diethoxyethoxy)-1-[(4-methoxyphenyl)-methyl]benzo[cd]indol-2-one(1 g, 2.37 mmol) was added at RT. Then the reaction mixture was heatedat 80° C. for 3 hr. TLC showed a new spot and starting was consumed. Thereaction mixture was cooled to 0° C. and quenched with ice-water andextracted with EtOAc. The organic part was washed with water and brinesolution and then it was dried over sodium sulfate and the organic partwas concentrated under reduced pressure to afford(Z)-3-(dimethylamino)-2-[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]oxy-prop-2-enal(800 mg, 1.69 mmol, 71.22% yield, 85% purity) as crude product; LCMS(ES+)=403.4 [M+H]+.

Step-3: Synthesis of tert-butyl4-(4-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)oxy)-1H-pyrazol-1-yl)piperidine-1-carboxylate:The (Z)-3-(dimethylamino)-2-[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]oxy-prop-2-enal(1.3 g, 3.23 mmol) was dissolved in a mixture of Methanol (20 mL) andWater (6 mL).Tert-butyl4-(5,6-dioxo-1,4,2,3-dioxadiazinan-2-yl)piperidine-1-carboxylate (973.27mg, 3.23 mmol) was then added, and the reaction mixture was stirred at90° C. for 16 hr. It was then concentrated under reduced pressure, andthe residue was purified by combiflash with eluting solvent EtOAc:hexaneto provide the title compound tert-butyl4-[4-[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]oxy-pyrazol-1-yl]piperidine-1-carboxylate(800 mg, 1.15 mmol, 35.72% yield, 80% purity) as a pale yellow solid;LCMS (ES+)=555.6 [M+H]+.

Step-4: Synthesis of6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)oxy)benzo[cd]indol-2(1H)-one: Toan ice cold solution of tert-butyl4-[4-[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]-oxy-pyrazol-1-yl]piperidine-1-carboxylate(180 mg, 324.54 umol) in TFA (6 mL) was added trifluromethane sulphonicacid (146.12 mg, 973.61 umol, 85.95 uL). The reaction was continued at25° C. for 16 hr. The reaction mass was evaporated to dryness and addedto saturated sodium bicarbonate solution and extracted with EtOAc. Theorganics was dried over sodium sulphate and evaporated to dryness to get6-[1-(4-piperidyl)pyrazol-4-yl]oxy-1H-benzo[cd]indol-2-one (100 mg,209.35 umol, 64.51% yield, 70% purity) as crude; LCMS (ES+)=335.3[M+H]+.

Step-5: Synthesis of6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)oxy)benzo-[cd]indol-2(1H)-one:To a solution of6-[1-(4-piperidyl)pyrazol-4-yl]oxy-1H-benzo[cd]indol-2-one (200 mg,598.14 umol) and 1-methylcyclobutanecarboxylic acid (68.27 mg, 598.14umol) in DMF (5 mL) was added DIPEA (231.92 mg, 1.79 mmol, 312.55 uL)and followed by HATU (250.17 mg, 657.95 umol) and stirred at 25° C. for16 hr. Crude LCMS showed formation of product. The reaction was dilutedwith water and extracted with EtOAc. The combined organics was washedwith water and brine and dried over sodium sulphate. The crude waspurified by combiflash with eluting solvent EtOAc:hexane to get6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]oxy-1H-benzo[cd]indol-2-one(70 mg, 157.72 umol, 26.37% yield, 97% purity) as dark brown solid; LCMS(ES+)=431.3 [M+H]+.

Step-6: Synthesis of3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)oxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To an ice cold solution of6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]oxy-1H-benzo-[cd]indol-2-one(70 mg, 162.60 umol) in THF (5 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (65.03 mg, 1.63 mmol, 60%purity) stirred at 25° C. for 10 mins. Compound3-bromopiperidine-2,6-dione (156.11 mg, 813.01 umol) was added at a timeand again stirred for 10 mins at 25° C. The reaction was then heated to70° C. for 0.5 hr. Crude LCMS showed formation of product. The reactionwas cooled to RT and diluted with water and extracted with EtOAc. Thecombined organics was washed with water and brine and dried over sodiumsulphate. Crude was evaporated to dryness and purified by Prep HPLC toget3-[6-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]oxy-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 207 (45 mg, 80.03 umol, 49.22% yield, 96.32% purity) as yellowsolid. 1H NMR (400 MHz, DMSO-d6): δ 11.10 (bs, 1H), 8.36 (d, J=8 Hz, 1H)8.18 (d, J=8 Hz, 1H), 7.96 (s, 1H), 7.91 (t, J=8 Hz, 1H), 7.49 (s, 1H),7.03 (d, J=8 Hz, 1H) 6.92 (d, J=8 Hz, 1H), 5.45-5.41 (m, 1H), 4.40-4.34(m, 2H), 3.61 (m, 1H), 3.12 (m, 1H), 2.97-2.90 (m, 1H), 2.76-2.62 (m,3H), 2.43-2.40 (m, 2H), 2.10-2.03 (m, 3H), 1.95-1.90 (m, 1H), 1.88-1.79(m, 4H), 1.62 (m, 1H), 1.36 (s, 3H); LCMS (ES+)=542.2 [M+H]+.

Example 113. Synthesis of4-(4-((1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1-H-pyrazol-3-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile(Compound 208) and4-(4-((1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1-H-pyrazol-5-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile(Compound 209)

Step-1: Synthesis of3-fluoro-4-(4-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)piperazin-1-yl)benzonitrile:To a solution of 3-fluoro-4-piperazin-1-yl-benzonitrile; hydrochloride(3.61 g, 14.95 mmol) in DMF (25 mL) was added DIPEA (5.80 g, 44.85 mmol,7.81 mL) and stirred at RT for 10 mins. Compound5-(chloromethyl)-1-tetrahydropyran-2-yl-pyrazole (5 g, 14.95 mmol) wasadded to the reaction and stirred at ambient tempr for 18 h. Crude LCMSshowed formation of product. The reaction was cooled, added to water andextracted with EtOAc. The combined organics was washed with water, brineand dried over sodium sulphate. The crude was purified by combiflashwith eluting solvent MeOH/DCM to get3-fluoro-4-[4-[(2-tetrahydropyran-2-ylpyrazol-3-yl)methyl]piperazin-1-yl]benzonitrile(3.6 g, 9.26 mmol, 61.92% yield, 95% purity) as sticky gel; LCMS(ES+)=370.2 [M+H]+.

Step-2: Synthesis of4-(4-((1H-pyrazol-5-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile: To asolution of3-fluoro-4-[4-[(2-tetrahydropyran-2-ylpyrazol-3-yl)methyl]piperazin-1-yl]benzonitrile(4.2 g, 11.37 mmol) in Ethanol (30 mL) was added HCl (34.54 mg, 34.11mmol, 43.18 uL, 36 purity) and stirred at 25° C. for 16 h. Completion ofreaction was confirmed by TLC. The reaction mass was evaporated todryness. The crude mass was dissolved in EtOAc and washed by bicarbonatesolution and brine and dried over sodium sulphate and evaporated crudewas purified by combiflash with MeOH in DCM to get3-fluoro-4-[4-(1H-pyrazol-5-ylmethyl)piperazin-1-yl]benzonitrile (2.8 g,8.54 mmol, 75.10% yield, 87% purity) as sticky solid; LCMS (ES+)=286.8[M+H]+.

Step-3: Synthesis of3-fluoro-4-(4-((1-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)piperazin-1-yl)benzonitrileand3-fluoro-4-(4-((1-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-5-yl)methyl)piperazin-1-yl)benzonitrile:To the stirred solution of3-fluoro-4-[4-(1H-pyrazol-5-ylmethyl)piperazin-1-yl]benzonitrile (1.5 g,5.26 mmol) and6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1.78g, 5.26 mmol) in DMF (25 mL) was added Cesium carbonate (5.14 g, 15.77mmol). It was heated at 90° C. for 16 hr. It was cooled to RT, dilutedwith EtOAc, washed with water, brine, dried over sodium sulfate andconcentrated under reduced pressure, Crude was purified by combiflashwith eluting solvent EtOAc/hexane and 5% MeOH in DCM to afford3-fluoro-4-[4-[[2-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]-pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile(260 mg, 416.60 umol, 7.92% yield, 94% purity) as brown solid and polarspot was again purified by Prep HPLC to get3-fluoro-4-[4-[[2-[[1-[(4-methoxy-phenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile(260 mg, 416.60 umol, 7.92% yield, 94% purity) as yellow solid; LCMS(ES+)=587.2 [M+H]+.

Step-4a: Synthesis of3-fluoro-4-(4-((1-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)piperazin-1-yl)benzonitrile:To an ice cold solution of3-fluoro-4-[4-[[1-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]meth-yl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile(350.00 mg, 596.60 umol) in TFA (15 mL) was addedTrifluoromethanesulfonic acid, 98+% (268.61 mg, 1.79 mmol, 157.08 uL).The reaction was continued at 25° C. for 16 hr. The reaction mass wasevaporated to dryness and added to saturated sodium bicarbonate solutionand extracted with EtOAc. The organics was dried over sodium sulphateand evaporated to dryness to get3-fluoro-4-[4-[[1-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-3-yl]methyl]-piperazin-1-yl]benzonitrile(270 mg, 463.01 umol, 77.61% yield, 80% purity) as crude; LCMS(ES+)=467.3 [M+H]+.

Step-4b: Synthesis of3-fluoro-4-(4-((1-((2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-5-yl)methyl)piperazin-1-yl)benzonitrile:To an ice cold solution of3-fluoro-4-[4-[[2-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]meth-yl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile(250 mg, 426.14 umol) in TFA (5 mL) was added Trifluoromethanesulfonicacid, 98+% (191.87 mg, 1.28 mmol, 112.20 uL). The reaction was continuedat 25° C. for 16 hr. The reaction mass was evaporated to dryness andadded to saturated sodium bi-carbonate solution and extracted withEtOAc. The organics was dried over sodium sulphate and evaporated todryness to get3-fluoro-4-[4-[[2-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile(192 mg, 370.41 umol, 86.92% yield, 90% purity) as crude; LCMS(ES+)=467.3 [M+H]+.

Step-5a: Synthesis of4-(4-((1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1-H-pyrazol-3-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile:To an ice cold solution of3-fluoro-4-[4-[[1-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-3-yl]methyl]-piperazin-1-yl]benzonitrile(100.00 mg, 214.36 umol) in THF (30 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (82.13 mg, 2.14 mmol, 60%purity) stirred at 25° C. for 10 mins. Compound3-bromopiperidine-2,6-dione (205.80 mg, 1.07 mmol) was added at a timeand again stirred for 10 mins at 25° C. The reaction was then heated to70° C. for 0.5 hr. Crude LCMS showed formation of product. The reactionwas cooled to RT and diluted with water and extracted with EtOAc. Thecombined organics was washed with water and brine and dried over sodiumsulphate. Crude was evaporated to dryness and purified by Prep HPLC toget4-[4-[[1-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-3-yl]methyl]piperazin-1-yl]-3-fluoro-benzonitrileCompound 208 (16 mg, 27.51 umol, 12.83% yield, 99.3% purity) as yellowsolid. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (bs, 1H), 8.41 (d, J=8 Hz, 1H)8.10 (d, J=8 Hz, 1H), 7.85 (t, J=8 Hz, 1H), 7.78 (s, 1H), 7.68 (d, J=12Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.45 (d, J=8 Hz, 1H), 7.14-7.06 (m, 2H),6.16 (s, 1H), 5.72 (s, 2H), 5.46-5.44 (m, 1H), 3.46 (s, 2H), 3.13 (bs,4H), 2.94-2.92 (m, 1H), 2.79-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.43 (bs,4H), 2.08-2.01 (m, 1H). LCMS (ES+)=578.2 [M+H]+.

Step-5b: Synthesis of4-(4-((1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1-H-pyrazol-5-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile:To an ice cold solution of3-fluoro-4-[4-[[2-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-3-yl]methyl]piperazin-1-yl]benzonitrile(200 mg, 428.72 umol) in THF (10 mL) was added sodium hydride (185.85mg, 4.29 mmol, 60% purity) stirred at 25° C. for 10 mins. Compound3-bromopiperidine-2,6-dione (411.59 mg, 2.14 mmol) was added at a timeand again stirred for 10 mins at 25° C. The reaction was then heated to70° C. for 0.5 hr. Crude LCMS showed formation of product. The reactionwas cooled to RT and diluted with water and extracted with EtOAc. Thecombined organics was washed with water and brine and dried over sodiumsulphate. Crude was evaporated to dryness and purified by Prep HPLC toget4-[4-[[2-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-3-yl]methyl]piperazin-1-yl]-3-fluoro-benzonitrileCompound 209 (31 mg, 53.32 umol, 12.44% yield, 99.34% purity) as yellowsolid. 1H NMR (400 MHz, DMSO-d6): δ 11.10 (bs, 1H), 8.47 (d, J=8 Hz, 1H)8.09 (d, J=8 Hz, 1H), 7.86 (t, J=8 Hz, 1H), 7.67 (dd, J=12 Hz, J1=1.6Hz, 1H),7.53 (dd, J=8 Hz, J1=1.6 Hz, 1H), 7.43 (s, 1H), 7.22 (d, J=4 Hz,1H), 7.09 (d, J=8 Hz, 1H), 7.01 (t, J=8 Hz, 1H), 6.24 (s, 1H), 5.83 (s,2H), 5.45-5.41 (m, 1H), 3.56 (s, 2H), 2.96-2.89 (m, 1H), 2.85 (bs, 4H),2.76-2.61 (m, 2H), 2.42 (bs, 4H), 2.07-2.01 (m, 1H). LCMS (ES+)=578.2[M+H]+.

Example 114. Synthesis of3-(2-oxo-6-(4-((4-phenylpiperazin-1-yl)methyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 210)

Step-1: Synthesis of 1-(4-(chloromethyl)benzyl)-4-phenylpiperazine: Tothe stirred solution of 1-phenylpiperazine (2 g, 12.33 mmol) in DMF (20mL), DIPEA (4.78 g, 36.98 mmol, 6.44 mL) was added followed by1,4-bis(chloromethyl)benzene (4.32 g, 24.66 mmol, 3.04 mL). Theresulting reaction mixture was heated at 60° C. for 12 hr. Aftercompletion of reaction, ice cooled water was added to RM and extractedwith EtOAc. Organic portion was separated, dried over sodium sulfate andconcentrated. Crude LCMS showed formation of product. Crude mass wasevaporated and purified by combiflash with eluting solvent 10-30% EtOAcin hexane to afford1-[[4-(chloromethyl)phenyl]methyl]-4-phenyl-piperazine (1.6 g, 4.79mmol, 38.83% yield, 90% purity) as off white solid; LCMS (ES+)=301.4[M+H]+.

Step-2: Synthesis of6-(4-((4-phenylpiperazin-1-yl)methyl)benzyl)benzo[cd]indol-2(1H)-one: Toa stirred solution of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(735.83 mg, 2.49 mmol) and1-[[4-(chloromethyl)phenyl]methyl]-4-phenyl-piperazine (500 mg, 1.66mmol) in Ethanol (2 mL) and Toluene (7 mL) was added tri potassium;phosphate (882.02 mg, 4.16 mmol) and degassed under nitrogen atmosphereover 10 minutes. Then tris-o-tolylphosphane (101.18 mg, 332.42 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (152.20 mg, 166.21umol) was added to the reaction mass and heated the resultant reactionmixture 90° C. for 16 hr. After completion of reaction, reaction masswas filtered through celite bed. Filtrate was collected and diluted withEtOAc and washed with water and brine. Combined organic solvent wasseparated, dried over sodium sulfate and concentrated under vacuum.Crude was purified by combiflash with eluting solvent 10-50% EtOAc inhexane to afford6-[[4-[(4-phenylpiperazin-1-yl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(370 mg, 768.09 umol, 46.21% yield, 90% purity) as brown gel.

Step-3: Synthesis of3-(2-oxo-6-(4-((4-phenylpiperazin-1-yl)methyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To an ice cold solution of6-[[4-[(4-phenylpiperazin-1-yl)methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(100.00 mg, 230.66 umol) in THF(30 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (8.84 mg, 220.97 umol, 60%purity) stirred at 25° C. for 10 mins. Compound3-bromopiperidine-2,6-dione (221.44 mg, 1.15 mmol) was added at a timeand again stirred for 10 mins at 25° C. The reaction was then heated to70° C. for 0.5 hr. Crude LCMS showed formation of product. The reactionwas cooled to RT and diluted with water and extracted with EtOAc. Thecombined organics was washed with water and brine and dried over sodiumsulphate. Crude was evaporated to dryness and purified by Prep HPLC toget3-[2-oxo-6-[[4-[(4-phenylpiperazin-1-yl)methyl]phenyl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 210 (46 mg, 84.30 umol, 36.55% yield, 99.81% purity) as yellowsolid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (bs, 1H), 8.34 (d, J=8 Hz,1H), 8.08 (d, J=8 Hz, 1H), 7.83 (t, J=8 Hz, 1H), 7.42 (d, J=8 Hz, 1H),7.26 (m, 6H), 7.11 (d, J=8 Hz, 1H), 6.89 (d, J=8 Hz, 2H), 6.76 (t, J=8Hz, 1H), 5.45-5.43 (m, 1H), 4.38 (s, 2H), 3.44 (s, 2H), 3.08 (bs, 4H),2.98-2.90 (m, 1H), 2.80-2.73 (m, 1H), 2.70-2.57 (m, 1H), 2.45 (bs, 4H),2.10 (m, 1H); LCMS (ES+)=545.3 [M+H]+.

Example 115. Synthesis of3-(6-((1-(4-methyl-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 211)

Step-1: Synthesis of tert-butyl4-amino-4-methylpiperidine-1-carboxylate: To 50 ml of a 50%tetrahydrofuran aqueous solution of Mercury(II) acetate, 98+% (1.78 g,5.58 mmol, 541.75 uL), Sodium azide (988.62 mg, 15.21 mmol, 534.39 uL)and tert-butyl 4-methylenepiperidine-1-carboxylate (1 g, 5.07 mmol) wereadded, followed by stirring for 17 hours under heating at 900 C. Aftercooling to room temperature, 0.71 ml of a 15% potassium hydroxideaqueous solution, and further a suspension of Sodium Borohydride (143.83mg, 3.80 mmol, 134.42 uL) in 0.71 ml of a 15% potassium hydroxideaqueous solution, were added, followed by stirring for 30 minutes atroom temperature. The reaction mixture was diluted with diethyl ether,washed with water and brine, and dried over anhydrous sodium sulfate,followed by distilling off the solvent under reduced pressure to givetert-butyl 4-amino-4-methylpiperidine-1-carboxylate (1.1 g, 2.75 mmol,54.18% yield, 60% purity) as title compound.

Step-2: Synthesis of tert-butyl4-azido-4-methylpiperidine-1-carboxylate: Trifluoromethanesulfonicanhydride (1.32 g, 4.67 mmol, 783.65 uL) was added to a mixture ofsodium azide (758.38 mg, 11.67 mmol, 409.94 uL), H2O (14 mL), and DCM(25 mL) at 0 C. The mixture was stirred at 0° C. for 2 h, then thelayers are separated. The aqueous layer was extracted with CH2Cl2 (2×10mL). The combined extracts were washed with saturated aqueous Na2CO3,then added to a stirring mixture of tert-butyl4-amino-4-methyl-piperidine-1-carboxylate (500 mg, 2.33 mmol), Potassiumcarbonate-granular (483.68 mg, 3.50 mmol, 211.21 uL), copper sulphate(37.24 mg, 233.31 umol, 10.34 uL), H₂O (27 mL), and Methanol (45 mL).The resulting mixture was stirred for 16 h, then evaporated, and dilutedwith H2O (50 mL) and extracted with DCM. Combined organics was washedwith water and dried over sodium sulphate. Organics was evaporated todryness to get tert-butyl 4-azido-4-methylpiperidine-1-carboxylate ascrude; LCMS (ES+)=241.4 [M+H]+.

Step-3: Synthesis of tert-butyl4-(4-(hydroxy(l-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-1,2,3-triazol-1-yl)-4-methylpiperidine-1-carboxylate: To thestirred solution of tert-butyl 4-azido-4-methyl-piperidine-1-carboxylate(200 mg, 832.29 umol) and6-(1-hydroxyprop-2-ynyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(285.79 mg, 832.29 umol) in THF (5 mL), solution of copper sulphate.5H₂O (20.78 mg, 83.23 umol, 5.77 uL) in Water (1 mL) was added andstirred for 15 minutes followed by the addition of s odium;(2R)-2-[1,2-di hydroxy ethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (65.95mg, 332.92 umol). The reaction mass was kept on stirring for further 24h at 25° C. After complete consumption of SM, reaction mass was filteredthrough celite bed dried over sodium sulphate. Filtrate was evaporatedand the crude residue was purified by combiflash with eluting solvent30-100% EtOAc in hexane to afford tert-butyl4-[4-[hydroxy-[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]triazol-1-yl]-4-methyl-piperidine-1-carboxylate(97 mg, 113.01 umol, 13.58% yield, 68% purity) as sticky gel; LCMS(ES+)=584.4 [M+H]+.

Step-4: Synthesis of6-((1-(4-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)benzo[cd]indol-2(1H)-one:To solution of tert-butyl4-[4-[hydroxy-[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]-triazol-1-yl]-4-methyl-piperidine-1-carboxylate(50 mg, 85.66 umol) in TFA (78.14 mg, 685.31 umol, 52.80 uL) was addedtriethyl silane (39.84 mg, 342.66 umol, 54.73 uL) in a sealed tube. Thereaction was heated to 90° C. for 2 hr. Crude LCMS showed formation ofproduct. The reaction was evaporated to dryness and neutralized bysodium bicarbonate solution and extracted by EtOAc. Combined organicswas dried over sodium sulphate and evaporated to dryness and trituratedwith pentane to get6-[[1-(4-methyl-4-piperidyl)triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(22 mg, 50.66 umol, 59.14% yield, 80% purity) as brown solid; LCMS(ES+)=348.4 [M+H]+.

Step-5: Synthesis of6-((1-(4-methyl-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)benzo[cd]indol-2(1H)-one:To a solution of6-[[1-(4-methyl-4-piperidyl)triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(300 mg, 863.53 umol) in DMF (10 mL) was added1-(trifluoromethyl)cyclopropanecarboxylic acid (146.36 mg, 949.88 umol)and DIPEA (334.81 mg, 2.59 mmol, 451.23 uL) followed by HATU (492.51 mg,1.30 mmol) and stirred at 25° C. for 16 h. Crude LCMS showed formationof product. The reaction mass was added to water and extracted withEtOAc. The combined organics was washed with water, brine and dried oversodium sulphate. Crude was evaporated to dryness and purified bycombiflash with eluting solvent EtOAc in hexane to get6-[[1-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(130 mg, 241.99 umol, 28.02% yield, 90% purity) as dark brown gel; LCMS(ES+)=484.1 [M+H]+.

Step-6: Synthesis of3-(6-((1-(4-methyl-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To an ice cold solution of6-[[1-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(130 mg, 268.88 umol) in DMF (10 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (103.03 mg, 2.69 mmol, 60%purity) stirred at 25° C. for 10 mins. Compound3-bromopiperidine-2,6-dione (258.14 mg, 1.34 mmol) was added at a timeand again stirred for 10 mins at 25° C. The reaction was then heated to70° C. for 0.5 hr. Crude LCMS showed formation of product. The reactionwas cooled to RT and diluted with water and extracted with EtOAc. Thecombined organics was washed with water and brine and dried over sodiumsulphate. Crude was evaporated to dryness and purified by Prep HPLC toget3-[6-[[1-[4-methyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]-4-piperidyl]triazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 211 (20 mg, 33.55 umol, 12.48% yield, 99.74% purity) as yellowsolid. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (bs, 1H), 8.42 (d, J=12 Hz,1H), 8.10-8.08 (d, J=8 Hz, 2H), 7.85 (t, J=8 Hz, 1H), 7.39 (d, J=8 Hz,1H), 7.10 (d, J=8 Hz, 1H), 5.45-5.43 (m, 1H), 4.43 (s, 2H), 3.77 (m,2H), 2.94-2.92 (m, 1H), 2.76-2.72 (m, 1H), 2.67-2.62 (m, 1H), 2.37 (bs,2H), 2.09 (bs, 1H), 1.90 (bs, 2H), 1.45 (s, 3H), 1.26 (bs, 2H), 1.17(bs, 2H); LCMS (ES+)=595.3 [M+H]+.

Example 116. Synthesis of3-[6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 212) and3-[6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 213)

Step-1: Synthesis of1-[(4-methoxyphenyl)methyl]-6-[(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]benzo[cd]indol-2-one:In a sealed tube a stirred solution of1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (4.12 g, 14.80 mmol) and6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (5 g,14.80 mmol) in the mixture of solvent Toluene (100 mL) and Ethanol (50mL), was added Potassium phosphate tribasic anhydrous (7.85 g, 37.00mmol), reaction was degassed under argon atmosphere for 10 mins. Thenadded Tris(dibenzylideneacetone)dipalladium(0) (1.36 g, 1.48 mmol) aqndTris(o-tolyl)phosphine (901.04 mg, 2.96 mmol), again degassed for 5mins. Then tube was closed and heated to 110° C. for 16 hr. Aftercompletion of SM, reaction was filtered through celite bed andconcentrated under reduced pressure to give the crude. It was purifiedby combiflash column chromatography (using 30% EA in hexane) to give thetitle compound1-[(4-methoxyphenyl)methyl]-6-[(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]benzo[cd]indol-2-one(4.7 g, 9.33 mmol, 63.01% yield, 90% purity) as yellow solid; LC-MS:(ES+)=454.4 [M+H]+.

Step-2: Synthesis of1-Piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde: To a stirredsolution of tert-butyl4-(3-formylpyrrolo[2,3-b]pyridin-1-yl)piperidine-1-carboxylate 3 (525mg, 1.59 mmol) in 1,4 dioxane (10 mL) was added HCl in dioxane (4 M,11.95 mL). The reaction mixture was stirred at 25° C. for 16 hr. Aftercompletion of SM, the reaction was concentrated under reduced pressureand then washed with 10-20% ethyl acetate in n-hexane and finally driedto give the title compound1-(4-piperidyl)pyrrolo[2,3-b]pyridine-3-carbaldehyde (350 mg, 1.53 mmol,95.78% yield) as off-white solid; LCMS (ES+)=230.0 [M+H]+.

Step-3: Synthesis of6-[[1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one:To a stirred solution of1-[(4-methoxyphenyl)methyl]-6-(1H-pyrazol-4-ylmethyl)benzo[cd]indol-2-one(2.7 g, 7.31 mmol) and 1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate(3.45 g, 14.62 mmol) in DMF (20 mL), was added Cesium carbonate (4.76 g,14.62 mmol), reaction mixture was heated to 90° C. for 16 hr. Aftercompletion of SM, reaction mixture was quenched with water and extractedwith ethyl acetate, dried over sodium sulphate, concentrated underreduced pressure to give the crude. It was purified by combiflash columnchromatography (50% ethyl acetate in hexane) to give the title compound6-[[1-(1,4-dioxaspiro[4,5]decan-8-yl)pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(1.5 g, 2.65 mmol, 36.25% yield, 90% purity) as yellow solid; LCMS(ES+)=510.3 [M+H]+.

Step-4: Synthesis of1-[(4-methoxyphenyl)methyl]-6-[[1-(4-oxocyclohexyl)pyrazol-4-yl]methyl]benzo[cd]indol-2-one:To a stirred solution of6-[[1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(1.5 g, 2.94 mmol) in THF (10 mL), was added HCl (5 M, 2.94 mL) and thereaction mixture was stirred at 25° C. for 20 hr. After completion ofSM, solvent was concentrated under reduced pressure and neutralized bysodium bicarbonate and extracted with ethyl acetate, dried over sodiumsulphate, concentrated under reduced pressure to give the title compound1-[(4-methoxyphenyl)methyl]-6-[[1-(4-oxocyclohexyl)pyrazol-4-yl]methyl]benzo[cd]indol-2-one(1 g, 1.93 mmol, 65.68% yield, 90% purity) as yellow solid; LCMS(ES+)=466.5 [M+H]+.

Step-5: Synthesis of6-[[1-(4-oxocyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one: Toa stirred solution of1-[(4-methoxyphenyl)methyl]-6-[[1-(4-oxocyclohexyl)pyrazol-4-yl]methyl]benzo[cd]indol-2-one(300 mg, 644.41 umol) in Trifluoroacetic acid (7 mL), was added Anisole(696.87 mg, 6.44 mmol, 701.07 uL), reaction mixture was stirred at 60°C. for 16 hr. After completion of SM, TFA was removed and dissolved inice cooled water and neutralized by saturated solution of sodiumbicarbonate and extracted with ethyl acetate; separate the organiclayer, dried over sodium sulphate, concentrated under reduced pressure,to give the crude. It was purified by combiflash column chromatography(using ethyl acetate) to give the title compound6-[[1-(4-oxocyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (80mg, 208.46 umol, 32.35% yield, 90% purity) as yellow solid; LCMS(ES+)=346.2 [M+H]+.

Step-6: Synthesis of6-[[1-(4-hydroxycyclohexyl)pyrazol-4-yl]methyl]-1H-benzo one: To astirred solution of6-[[1-(4-oxocyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(100.00 mg, 289.52 umol) in Ethanol (10 mL), reaction mixture was cooledto 0° C., sodium borohydride (21.91 mg, 579.05 umol, 20.47 uL) was addedto it and stirred at 25° C. for 2 hr. After completion of SM, reactionwas quenched with ice cold water and then solvent was removed underreduced pressure, then dissolved in water and extracted with ethylacetate, separate the organic layer, dried over sodium sulphate,concentrated under reduced pressure, to give the crude. It was purifiedby combiflash column chromatography (using ethyl acetate) to give thetitle compound6-[[1-(4-hydroxycyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(75 mg, 194.30 umol, 67.11% yield, 90% purity) as yellow sticky liquid;LCMS (ES+)=348.2 [M+H]+.

Step-7: Synthesis of6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one:To a stirred solution of6-[[1-(4-hydroxycyclohexyl)pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(750 mg, 1.60 mmol) was dissolved in Di-tert-butyl dicarbonate (805.21mg, 3.69 mmol, 846.70 uL) under mild heating (less than 40° C.). ThenErbium(III) trifluoromethanesulfonate (98.57 mg, 160.41 umol) was addedto the mixture under N₂ atmosphere and the mixture was stirred at 25° C.for 16 hr. The reaction was monitored by TLC. After that the mixture wasdiluted with Et2O and the Et2O layer was washed with H2O. The organicphase was dried over Na₂SO₄, filtered, and then evaporated under vacuumto give the crude. This crude was purified by combi-flash columnchromatography6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(200 mg, 351.37 umol, 21.90% yield, 92% purity) as yellow solid. LCMS(ES+)=524.5 [M+H]+. NOTE: Separated the isomer by Prep-HPLC purificationand individually proceeded for the next step.

Step-8: Synthesis of3-[6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(50.00 mg, 123.91 umol) in THF (10 mL), reaction mixture was cooled to0° C., then slowly added Sodium hydride (in oil dispersion) 60%dispersion in mineral oil (142.44 mg, 3.72 mmol, 60% purity). Thenreaction was stirred for 5 mins to 0° C., then added3-bromopiperidine-2,6-dione (118.96 mg, 619.55 umol) portion wise, againstirred for 5 mins. Then reaction mixture was heated to 60° C. for 1 hr.After that reaction was quenched by ice cold water and extracted withethyl acetate, separate the organic layer, dried over sodium sulphate,concentrated under reduced pressure to give the crude. This crude waspurified by prep-TLC plate (using 80% EA in Hexane) to give the titlecompound3-[6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 212 (15 mg, 27.70 umol, 22.36% yield, 95.04% purity) as yellowsolid; LCMS (ES+)=515.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s,1H), 8.36-8.34 (d, 1H), 8.09-8.07 (d, 1H), 7.82 (t, 1H), 7.48 (s, 1H),7.35-7.34 (d, 1H), 7.27 (s, 1H), 7.07-7.06 (d, 1H), 5.45-5.41 (m, 1H),4.17 (s, 2H), 3.98 (brs, 1H), 3.45 (brs, 1H), 2.94 (m, 1H), 2.75-2.72(m, 1H), 2.66-2.62 (m, 1H), 2.09-2.06 (m, 1H), 1.88-1.86 (m, 2H),1.78-1.73 (m, 4H), 1.34-1.23 (m, 3H), 1.11 (s, 9H).

Step-9: Synthesis of3-[6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(50.00 mg, 123.91 umol) in THF (10 mL), reaction mixture was cooled to0° C., then slowly added Sodium hydride (in oil dispersion) 60%dispersion in mineral oil (142.44 mg, 3.72 mmol, 60% purity). Thenreaction was stirred for 5 mins to 0° C., then added3-bromopiperidine-2,6-dione (118.96 mg, 619.55 umol) portion wise, againstirred for 5 mins. Then reaction mixture was heated to 60° C. for 1 hr.After that reaction was quenched by ice cold water and extracted withethyl acetate, separate the organic layer, dried over sodium sulphate,concentrated under reduced pressure to give the crude. This crude waspurified by prep-HPLC to give the title compound3-[6-[[1-(4-tert-butoxycyclohexyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 213 (5 mg, 9.63 umol, 7.77% yield, 99.09% purity) as yellowsolid. LCMS (ES+)=515.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.10 (s,1H), 8.39-8.37 (d, 1H), 8.09-8.07 (d, 1H), 7.83 (t, 1H), 7.53 (s, 1H),7.36-7.34 (d, 1H), 7.27 (s, 1H), 7.08-7.06 (d, 1H), 5.45-5.40 (m, 1H),4.18 (s, 2H), 4.08-3.98 (m, 1H), 3.73 (brs, 1H), 2.99-2.90 (m, 2H),2.79-2.69 (m, 1H), 2.66-2.62 (m, 1H), 2.09-2.05 (m, 1H), 2.01-1.95 (m,1H), 1.70-1.68 (m, 2H), 1.60-1.46 (m, 4H), 1.12 (s, 9H).

Example 117. Synthesis of3-fluoro-4-[4-[[2-fluoro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile(Compound 214)

Step-1: Synthesis of 4-(4-Cyano-2-fluoro-phenyl)-piperazine-1-carboxylicacid tert-butyl ester: To a stirred solution of 3,4-difluorobenzonitrile(5.23 g, 37.58 mmol) in DMSO (25 mL) was added Potassiumcarbonate-granular (10.39 g, 75.17 mmol, 4.54 mL) and tert-butylpiperazine-1-carboxylate (7 g, 37.58 mmol) and heated at 100° C. for 16hr. The reaction mixture was cooled and ice cold water was added, awhite solid precipitate was formed. The solid precipitate was filteredthrough a sintered funnel and washed with water and dried in rotavpourto afford the desired compound4-(4-Cyano-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butylester as a white solid. LCMS (ES+)=306.3 [M+H]+.

Step-2: Synthesis of 3-fluoro-4-piperazin-1-yl-benzonitrile: To astirred solution of4-(4-tert-butoxypiperazin-1-yl)-3-fluoro-benzonitrile; methane; hydrate(3.5 g, 11.31 mmol) in Dioxan (20 mL) was added HCl in Dioxan (4 M,28.28 mL) and stirred the reaction mixture at 25° C. for 16 hr. Aftercompletion of SM, reaction mixture was dried under reduced pressure,triturated with pentane to afford the desired compound3-fluoro-4-piperazin-1-yl-benzonitrile (2.5 g, 10.14 mmol, 89.60% yield,98% purity) as off-white solid.

Step-3: Synthesis of4-[4-[(4-bromo-2-fluoro-phenyl)methyl]piperazin-1-yl]-3-fluoro-benzonitrile:To stirred solution of 3-fluoro-4-piperazin-1-yl-benzonitrile (7 g,34.11 mmol) in DMF (70 mL) was added Potassium carbonate, anhydrous, 99%(11.79 g, 85.27 mmol, 5.15 mL) stirred for 10 minutes and then4-bromo-1-(bromomethyl)-2-fluoro-benzene (9.14 g, 34.11 mmol) was addedand stirred the reaction mixture at 60° C. for 8 hr. After completion ofSM, reaction mixture was quenched with ice cold water and solid wasfiltered. Then Again solid was washed with water, dried under rotavaourto give the title compound4-[4-[(4-bromo-2-fluoro-phenyl)methyl]piperazin-1-yl]-3-fluoro-benzonitrile(9 g, 21.80 mmol, 63.91% yield, 95% purity) as a white solid. LCMS(ES+)=394.1 [M+H]+.

Step-4: Synthesis of3-fluoro-4-[4-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazin-1-yl]benzonitrite:To a stirred solution of4-[4-[(4-bromo-2-fluoro-phenyl)methyl]piperazin-1-yl]-3-fluoro-benzonitrile(1 g, 2.55 mmol) and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(776.88 mg, 3.06 mmol) in 1,4-Doxane (5 mL) was added Potassium acetate(625.51 mg, 6.37 mmol, 398.41 uL) then degassed for 10 mins, later[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (208.04 mg, 254.95 umol) was added and againdegassed for 5 mins, after degassing the tube was closed with teflon capand stirred at 90° C. for 16 hr. The progress of the reaction wasmonitored by TLC, after reaction completion reaction mixture wasfiltered through celite bed and washed with ethyl acetate andconcentrated under reduced pressure to give the title compound3-fluoro-4-[4-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazin-1-yl]benzonitrile(1 g, 682.90 umol, 26.79% yield, 30% purity) as black sticky liquid.LC-MS: (ES+)=440.4 [M+H]+.

Step-5: Synthesis of(3-fluoro-4-[4-[[2-fluoro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]benzonitrile:In a sealed tube a stirred solution of3-fluoro-4-[4-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazin-1-yl]benzonitrile(1.30 g, 2.96 mmol) and6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1 g,2.96 mmol) in the mixture of solvent Toluene (10 mL) and Ethanol (5 mL),was added Potassium phosphate tribasic anhydrous (1.57 g, 7.40 mmol),reaction was degassed under argon atmosphere for 10 mins. Then addedTris(dibenzylideneacetone)dipalladium(0) (271.08 mg, 296.03 umol) aqndTris(o-tolyl)phosphine (180.20 mg, 592.07 umol), again degassed for 5mins. Then tube was closed and heated to 90° C. for 16 hr. Aftercompletion of SM, reaction was filtered through celite bed andconcentrated under reduced pressure to give the crude. It was purifiedby combiflash column chromatography (using 30% EA in hexane) to give thetitle compound3-fluoro-4[4-[[2-fluoro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]benzonitrile(800 mg, 1.17 mmol, 39.57% yield, 90% purity) as yellow solid. LCMS(ES+)=614.9 [M+H]+.

Step-6: Synthesis of3-fluoro-4-[4-[[2-fluoro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile:To a stirred solution of3-fluoro-4-[4-[[2-fluoro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]methyl]piperazin-1-yl]benzonitrile(300 mg, 488.06 umol) in TFA (10 mL), was addedTrifluoromethanesulphonic acid (366.23 mg, 2.44 mmol, 214.17 uL),reaction mixture was stirred at 25° C. for 16 hr. After completion ofSM, TFA was removed and dissolved in ice cooled water and neutralised bysaturated solution of sodium bicarbonate and extracted with ethylacetate, separate the organic layer, dried over sodium sulphate,concentrated under reduced pressure, to give the crude. It was purifiedby combiflash column chromatography (using ethyl acetate) to give thetitle compound3-fluoro-4-[4-[[2-fluoro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile(210 mg, 394.92 umol, 80.92% yield, 93% purity) as yellow solid. LCMS(ES+)=495.1 [M+H]+.

Step-7: Synthesis of3-fluoro-4-[4-[[2-fluoro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile:To a stirred solution of3-fluoro-4-[4-[[2-fluoro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]methyl]piperazin-1-yl]benzonitrile(210 mg, 424.64 umol) in THF (20 mL), reaction mixture was cooled to 0°C., then slowly added Sodium hydride (in oil dispersion) 60% dispersionin mineral oil (488.12 mg, 12.74 mmol, 60% purity). Then reaction wasstirred for 2 mins in without ice bath and then again cooled to 0° C.,then added 3-bromopiperidine-2,6-dione (407.68 mg, 2.12 mmol) portionwise, again stirred for 2 mins in without ice bath. Then reactionmixture was heated to 60° C. for 1 hr. After that reaction was quenchedby ice cold water and extracted with ethyl acetate, separate the organiclayer, dried over sodium sulphate, concentrated under reduced pressureto give the crude. This crude was purified by combiflash columnchromatography (50% EA in Hexane) to give the title compound4-[4-[[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]-2-fluoro-phenyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrileCompound 214 (48 mg, 77.74 umol, 18.31% yield, 98.09% purity) as lightyellow solid. LCMS (ES+)=606.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ11.13 (s, 1H), 8.36-8.34 (d, 1H), 8.09-8.07 (d, 1H), 7.82 (t, 1H),7.69-7.65 (d, 1H), 7.55-7.53 (d, 1H), 7.45-7.44 (d, 1H), 7.30 (t, 1H),7.14-7.09 (m, 4H), 5.45 (t, 1H), 4.40 (s, 2H), 3.50 (s, 2H), 3.12 (brs,4H), 2.95-2.91 (m, 1H), 2.77-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.50 (brs,4H), 2.10-2.07 (m, 1H).

Example 118. Synthesis of3-(6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 215),3-[6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione)(Compound 216) and3-[6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 217)

Step 1: Synthesis of 6-bromo-1H-benzo[cd]indol-2-one (2): To a stirredsuspension of 1H-benzo[cd]indol-2-one (1) (250 g, 1.48 mol) inChloroform (2.5 L), a solution of molecular bromine (354.23 g, 2.22 mol,113.53 mL) in Chloroform (500 mL) was added drop wise at 0° C. and thereaction mixture was stirred at room temperature for 16 hours. Aftercompletion of the reaction (monitored by TLC), the reaction mass waspoured into saturated aqs. solution of Sodium thiosulphate. The yellowsolid formed was filtered through cintered funnel, washed with water,pentane and stripped with toluene to afford6-bromo-1H-benzo[cd]indol-2-one (2) (350 g, 90% yield) as yellow solid.LC MS: ES+ 2 (248.2 and 250.2).

Step 2: Synthesis of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo one: To astirred solution of 6-bromo-1H-benzo[cd]indol-2-one (2) (100 g, 403.10mmol) in 1,4-Dioxane (1 L) was added Bis(pinacolato)diboron (153.55 g,604.66 mmol) followed by well dried Potassium Acetate (118.68 g, 1.21mol, 75.60 mL). The resultant reaction mass was degassed well with argonfor 15 minutes. PdCl2(dppf).DCM (32.92 g, 40.31 mmol) was added and thereaction mass was heated at 100° C. for 16 hours. After completion ofthe reaction (monitored by TLC), the reaction mixture was cooled to RT,filtered through a pad of celite, washed with Ethyl acetate. Thecombined filtrate was then washed with cold water, dried over anhydroussodium sulphate and concentrated under reduced pressure to afford crude6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(3) (110 g, 64% yield) as brown gum. This was forwarded without furtherpurification, LC MS: ES+ 295.7.

Step 3: Synthesis of8-(4-(chloromethyl)benzyl)-1-oxa-8-azaspiro[4.5]decane (6): To a stirredsolution of 1-oxa-8-azaspiro[4.5]decane; hydrochloride (5) (5 g, 28.14mmol) in dry grade Acetone (50 mL) was added DIPEA (3.64 g, 28.14 mmol,4.90 mL) followed by Potassium carbonate, anhydrous, 99% (11.67 g, 84.43mmol, 5.10 mL) at RT and the resultant reaction mixture was heated at50° C. for 20 minutes. 1,4-bis(chloromethyl)benzene (4) (9.85 g, 56.28mmol, 6.94 mL) was then added to the reaction mixture and heating wascontinued for 3 hours. After completion of reaction (monitored by TLCand LCMS), volatiles were removed under vacuum and the solid thusobtained was taken in Ethyl acetate (20 mL), washed with water (×3) andBrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. Crude mass was purified by column chromatography(silica, gradient: 0-5% MeOH in DCM) to afford8-[[4-(chloromethyl)phenyl]methyl]-1-oxa-8-azaspiro[4.5]decane (6) (4.68g, 16.56 mmol, 58.84% yield, 99% purity) as colorless sticky solid. LCMS: ES+ 280.4. Step 4: Synthesis of6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)benzo[cd]indol-2(1H)-one(8): To a well degassed solution of8-[[4-(chloromethyl)phenyl]methyl]-1-oxa-8-azaspiro[4.5]decane (6) (4.68g, 16.73 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(7) (9.87 g, 33.45 mmol) in ethanol (20.0 mL)-Toluene (40.0 mL),Potassium phosphate tribasic anhydrous (10.65 g, 50.18 mmol) was addedfollowed by the addition Tri-o-Tolyl phosphine (1.02 g, 3.35 mmol) andPd2(dba)3 (1.53 g, 1.67 mmol). The resulting mixture was then heated at90° C. for 12 hours. After completion of reaction (as monitored byLCMS), the reaction mixture was filtered through a bed of celite, washedwith Ethyl acetate.

The combined filtrate was washed with water and brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Crudemass was purified by column chromatography (silica, gradient: 0-5% MeOHin DCM) to obtain6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one(8) (2.83 g, 6.17 mmol, 36.91% yield, 90% purity) as yellow solid. LCMS: ES+ 413.0.

Step 5: Synthesis of3-(6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To a ice cooled solution of6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one(8) (2.83 g, 6.86 mmol) in dry THF (20 mL), Sodium hydride (60%dispersion in mineral oil) (2.63 g, 68.60 mmol, 60% purity) was addedportion wise, maintaining the temp <5° C. Once the addition is over, theresultant mixture was stirred for 15 minutes at RT. Then the reactionmixture was again cooled to 0° C. and 3-bromopiperidine-2,6-dione (9)(6.59 g, 34.30 mmol) was added to it portion wise. After completeaddition, resulting solution was heated at 70° C. for 1 hour. Aftercompletion (evidenced from TLC), the reaction mixture was again cooledto 0° C. and quenched with ice cooled water. Aqueous part was extractedwith ethyl acetate (3×20 mL). Combined extract was dried over anhydroussodium sulfate and concentrated under reduced pressure. Crude mass waswashed with diethyl ether/pentane to afford3-[6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 215 (2.7 g, 5.15 mmol, 75.1% yield) as yellow solid. LC MS: ES+524.3.

Step 6: Chiral separation: Synthesis of3-[6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione)and3-[6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:1.2 g of3-(6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dioneCompound 215 was separated into enantiomers by chiral normal phasePreparative HPLC method. Prep fractions were first evaporated separatelyunder reduced pressure to obtain solid mass. The solid was thensuspended in a mixture of Acetonirile and Water (2:3) and it was kept ina Dry-ice/Acetone bath until the Acetonitrile-Water mixture solidified.The frozen mixture was then freeze dried under lyophilizer for 20 hoursto afford3-[6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 216 (first eluted peak, RT=6.29 min, assigned tentatively as‘S’ ABS) (420 mg, % ee 99.28) and3-[6-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 217 (second eluted peak, RT=12.34 min, assigned tentatively as‘It’ ABS) (360 mg, % ee 99.04) as yellow solids.

Example 119. Synthesis of3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 218), enantiomer 13-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 219) and enantiomer 23-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(21-1)-yl)piperidine-2,6-dione(Compound 220)

Step 1: Synthesis of 6-bromo-1H-benzo[cd]indol-2-one (2): To a stirredsuspension of 1H-benzo[cd]indol-2-one (1) (250 g, 1.48 mol) inChloroform (2.5 L), a solution of molecular bromine (354.23 g, 2.22 mol,113.53 mL) in Chloroform (500 mL) was added drop wise at 0° C. and thereaction mixture was stirred at room temperature for 16 hours. Aftercompletion of the reaction (monitored by TLC), the reaction mass waspoured into saturated aqs. solution of Sodium thiosulphate. The yellowsolid formed was filtered through sintered funnel, washed with water,pentane and stripped with toluene to afford6-bromo-1H-benzo[cd]indol-2-one (2) (350 g, 90% yield) as yellow solidwhich was stored in a Tarson plastic bottle at ambient temperature. LCMS: ES+ 2 (248.2 and 250.2).

Step 2: Synthesis of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(3): To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (2) (20 g,80.62 mmol) in 1,4 dioxane (500 mL) was added Bis(pinacolato) diboron(30.71 g, 120.93 mmol) followed by well dried potassium acetate (23.74g, 241.86 mmol, 15.12 mL). The resultant reaction mass was degassed wellwith argon for 15 minutes. Pd₂(dba)₃ (6.58 g, 8.06 mmol) was added andthe reaction mass was heated at 100° C. for 16 hours. After completionof the reaction (monitored by TLC), the reaction mixture was cooled toRT, filtered through a pad of celite, washed with Ethyl acetate (1 L).The combined filtrate was then washed with cold water (3×300 mL), driedover anhydrous sodium sulphate and concentrated under reduced pressureto afford crude6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(3) (23 g, 46.76 mmol, 58.00% yield) as brown gum which was stored in around bottomed flask at 5° C. inside a refrigerator. This was forwardedwithout further purification; LC MS: ES+ 295.7.

Step 3: Synthesis of 4-(4-(chloromethyl)benzyl)morpholine (6): To astirred solution of Morpholine (5) (8 g, 91.83 mmol, 8.03 mL) inanalytical grade acetone (15 mL) was added Potassium carbonate,anhydrous, 99% (12.69 g, 91.83 mmol, 5.54 mL) at RT and the resultantreaction mixture was heated at 50° C. for 20 minutes.1,4-bis(chloromethyl)benzene (4) (16.07 g, 91.83 mmol, 11.32 mL) wasthen added to the reaction mixture and heating was continued for 3hours. After completion of reaction (monitored by TLC and LCMS),volatiles were removed under vacuum and the solid thus obtained wastaken in Ethyl acetate (50 mL), washed with water (3×25 ml) and Brine(2×15 mL), dried over anhydrous sodium sulfate and concentrated underreduced pressure. Crude mass was purified by column chromatography(silica, gradient: 10-30% Ethyl acetate in Hexane) to afford4-[[4-(chloromethyl)phenyl]methyl]morpholine (6) (10 g, 44.30 mmol,48.25% yield) as colourless sticky solid which was stored in a roundbottomed flask at 5° C. inside a refrigerator; LC MS: ES+ 226.2.

Step 4: Synthesis of6-(4-(morpholinomethyl)benzyl)benzo[cd]indol-2(1H)-one (7): To a welldegassed solution of 4-[[4-(chloromethyl)phenyl]methyl]morpholine (6) (8g, 35.44 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(3) (20.92 g, 70.89 mmol) in Ethanol (20 mL)-Toluene (40 mL), Potassiumphosphate tribasic, anhydrous, (22.57 g, 106.33 mmol) was added followedby the addition of Tri-o-Tolyl phosphine (2.16 g, 7.09 mmol) andPd₂(dba)₃ (3.25 g, 3.54 mmol). The resulting mixture was then heated at90° C. for 12 hours. After completion of reaction (as monitored byLCMS), the reaction mixture was filtered through a bed of celite, washedwith Ethyl acetate (200 mL). The combined filtrate was then washed withwater (3×50 mL) and brine (2×40 mL), dried over anhydrous sodium sulfateand concentrated under reduced pressure. Crude mass was purified bycolumn chromatography (silica, gradient: 0-20% Ethyl acetate in DCM) toobtain 6-[[4-(morpholinomethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one(7) (6.5 g, 17.59 mmol, 49.63% yield) as yellow solid which was storedin a Tarson plastic bottle at ambient temperature. LC MS: ES+ 359.3.

Step 5: Synthesis of3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To a ice cooled solution of6-[[4-(morpholinomethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (7) (4.8g, 13.39 mmol) in dry THF (50 mL), Sodium hydride (60% dispersion inmineral oil) (3.08 g, 133.92 mmol) was added portion wise, maintainingthe temp <5° C. Once the addition is over, the resultant mixture wasstirred for 15 minutes at RT. Then the reaction mixture was again cooledto 0° C. and 3-bromopiperidine-2,6-dione (8) (12.86 g, 66.96 mmol) wasadded to it portion wise. After complete addition, resulting solutionwas heated at 70° C. for 1 hour. After completion (evidenced from TLC),the reaction mixture was again cooled to 0° C. and quenched with icecooled water (40 mL). Aqueous part was extracted with ethyl acetate(3×50 mL). Combined extracts was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. Crude mass was purified by flashchromatography (silica, gradient: 2.5% MeOH in DCM) to afford3-[6-[[4-(morpholinomethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 218 (4 g, 8.36 mmol, 62.44% yield) as yellow solid which wasstored in a round bottomed flask at 5° C. inside a refrigerator. ¹H NMR(400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 8.06 (d,J=6.92 Hz, 1H), 7.80 (t, J=7.58 Hz, 1H), 7.39 (d, J=7.24 Hz, 1H),7.24-7.17 (m, 4H), 7.10 (d, J=7.2 Hz, 1H), 5.44 (dd, J=12.36, 4.76 Hz,1H), 4.36 (s, 1H), 3.51 (br s, 4H), 3.36 (s, 2H), 2.98-2.90 (m, 1H),2.79-2.73 (m, 1H), 2.69-2.62 (m, 1H), 2.28 (br s, 4H), 2.10-2.07 (m,1H); LC MS: ES+ 470.2.

Step 6: Chiral separation: Preparation of3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dioneand3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:3.8 g of3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dioneCompound 218 was separated into enantiomers by chiral normal phasePreparative HPLC method. Prep fractions were first evaporated separatelyunder reduced pressure to obtain solid mass. The solid was thensuspended in a mixture of Acetonirile and Water (2:3) and it was kept ina Dry-ice/Acetone bath until the Acetonitrile-Water mixture solidified.The frozen mixture was then freeze dried under lyophilizer for 20 hoursto afford3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dioneCompound 219 (first eluted peak, RT=9.33 min, assigned tentatively as S′ABS) (1.3 g, % ee 99.9) and3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dioneCompound 220 (second eluted peak, RT=21.99 min, assigned tentatively as‘R’ ABS) (1.3 g, % ee 99.76) as yellow solids which were transferred in20 mL clear bar-coded glass vials and stored under Nitrogen Desiccatorsat approximately 22° C.

Example 120. Synthesis of3-[20-[[4-(morpholinomethyl)phenyl]methyl]-25-oxo-27,30-diazatricyclododeca-(2),1(18),7(20),19(21),22(27)-pentaen-30-yl]piperidine-2,6-dione(Compound 221)

Step 1: Synthesis of26-[(4-methoxyphenyl)methyl]-15-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-25,26-diazatricyclododeca-6,8(19),13(15),18(20),21(25)-pentaen-22-one(2): To a stirred solution of14-bromo-19-[(4-methoxyphenyl)methyl]-18,19-diazatricyclododeca-1,3(13),8(14),12(15),16(18)-pentaen-17-one(1) (1 g, 2.71 mmol) in 1,4 dioxane (20 mL) was added Bis(pinacolato)diboron (1.03 g, 4.06 mmol) followed by well dried potassium acetate(797.45 mg, 8.13 mmol, 507.93 uL). The resultant reaction mass wasdegassed well with argon for 15 minutes. cyclopentyl(diphenyl)phosphane;di chloromethane; di chloropalladium; iron (221.18 mg, 270.85 umol) wasadded and the reaction mass was heated at 100° C. for 16 hours. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wascooled to RT, filtered through a pad of celite, washed with more Ethylacetate. The combined filtrate was washed with cold water, dried oversodium sulphate and concentrated under reduced pressure to afford crude26-[(4-methoxyphenyl)methyl]-15-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-25,26-diazatricyclododeca-6,8(19),13(15),18(20),21(25)-pentaen-22-one 2 (1.5 g(crude) g, 2.16 mmol, 79.82%yield, 60% purity) as brown gum. LC MS: ES+ 417.1.

Step 2: Synthesis of 4-[[4-(chloromethyl)phenyl]methyl]morpholine (3):To a stirred solution of morpholine 4 (5 g, 57.39 mmol, 5.02 mL) in drygrade ACETONE (200.0 mL) was added POTASSIUM CARBONATE (23.80 g, 172.18mmol, 10.39 mL) at RT and the resultant reaction mixture was heated at60° C. for 60 minutes. 1,4-bis(chloromethyl)benzene 3 (10.05 g, 57.39mmol, 7.08 mL) was then added to the reaction mixture and heating wascontinued for 16 hours. After completion of reaction (monitored by TLCand LCMS), volatiles were removed under vacuum and the solid thusobtained was taken in Ethyl acetate (70 mL), washed with water (×3) andBrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. Crude mass was purified by column chromatography(silica, gradient: 10-30% Ethyl acetate in Hexane) to afford4-[[4-(chloromethyl)phenyl]methyl]morpholine 5 (6.1 g, 25.67 mmol,44.73% yield, 95% purity) as colourless sticky solid. LC MS: ES+ 226.09.

Step 3: Synthesis of32-[(4-methoxyphenyl)methyl]-26-[[4-(morpholinomethyl)phenyl]methyl]-30,32-diazatricyclododeca-1(3),2(24),12(26),25(27),28(30)-pentaen-29-one:To a well degassed solution of4-[[4-(chloromethyl)phenyl]methyl]morpholine 5 (400 mg, 1.77 mmol) and2-[(4-methoxyphenyl)methyl]-15-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-25,26-diazatricyclododeca-6(8),7(18),13(15),19,21(25)-pentaen-22-one2 (1.48 g, 3.54 mmol) in ethanol (5.0 mL)-Toluene (10 mL), Potassiumphosphate tribasic anhydrous (1.13 g, 5.32 mmol) was added followed bythe addition Tri-o-Tolyl phosphine (107.88 mg, 354.43 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (162.28 mg, 177.22umol). The resulting mixture was then heated at 90° C. for 12 hours.After completion of reaction (as monitored by LCMS), the reactionmixture was filtered through a bed of celite, washed with Ethyl acetate(100 mL). The combined filtrate was washed with water (3×20 mL) andbrine (2×15 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure. Crude mass was purified by column chromatography(silica, gradient: 0-5% MeOH in DCM) to obtain32-[(4-methoxyphenyl)methyl]-26-[[4-(morpholinomethyl)phenyl]methyl]-30,32-diazatricyclododeca-1(3),2(24),12(26),25(27),28(30)-pentaen-29-one6 (420 mg, 788.21 umol, 44.48% yield, 90% purity) as yellow solid andstored in a round bottom glass at rt. LC MS: ES+ 480.1.

Step 4: Synthesis of18-[[4-(morpholinomethyl)phenyl]methyl]-22,23-diazatricyclododeca-(2),1(16),7(18),17(19),20(22)-pentaen-21-one(7): To the stirred solution of 32-[(4-methoxyphenyl)methyl]-26-[[4-(morpholinomethyl)phenyl]methyl]-30,32-diazatricyclododeca-1(3),2(24),12(26),25(27),28(30)-pentaen-29-one6 (420 mg, 875.79 umol) in TFA (10 mL) Triflic acid (1.97 g, 13.14 mmol,1.15 mL) drop wise and the reaction mixture was stirred at 25° C. for 16hours. After completion of reaction, the reaction mixture was evaporatedand quenched with saturated sodium bicarbonate solution. Aqueous partwas extracted with ethyl acetate (3×25 mL), washed with water followedby brine. The organic part was dried over sodium sulphate andconcentrated to afford crude18-[[4-(morpholinomethyl)phenyl]methyl]-22,23-diazatricyclododeca-(2),1(16),7(18),17(19),20(22)-pentaen-21-one7 (230 mg, 531.13 umol, 60.65% yield, 83% purity) as brown solid. LC MS:ES+ 360.2.

Step 5: Synthesis of3-[20-[[4-(morpholinomethyl)phenyl]methyl]-25-oxo-27,30-diazatricyclododeca-(2),1(18),7(20),19(21),22(27)-pentaen-30-yl]piperidine-2,6-dione:To a cooled solution of18-[[4-(morpholinomethyl)phenyl]methyl]-22,23-diazatricyclododeca-(2),1(16),7(18),17(19),20(22)-pentaen-21-one7 (200 mg, 556.45 umol) in dry THF (20 mL), Sodium hydride (in oildispersion) 60% dispersion in mineral oil (213.21 mg, 5.56 mmol, 60%purity) was added portion wise, maintaining the temp <5° C. Once theaddition is over, the resultant mixture was stirred for 15 minutes atRT. Then the reaction mixture was again cooled to 0° C. and3-bromopiperidine-2,6-dione 8 (534.22 mg, 2.78 mmol) was added to itportion wise. After complete addition, resulting solution was heated at70° C. 1 hour. After completion (evidenced from TLC), the reactionmixture was cooled to 0° C. and quenched with the addition of ice cooledwater. Aqueous part was extracted with ethyl acetate (3×50 mL). Combinedorganics was separated, dried over sodium sulphate and concentratedunder reduced pressure. Crude mass was purified by flash chromatography(silica, gradient: 0-2.5% MeOH in DCM) to afford Racemic3-[20-[[4-(morpholinomethyl)phenyl]methyl]-25-oxo-27,30-diazatricyclododeca-(2),1(18),7(20),19(21),22(27)-pentaen-30-yl]piperidine-2,6-dione

Compound 221 (16 mg, 31.87 umol, 5.73% yield, 93.73% purity). ¹H NMR(400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 8.15-8.12(m, 2H), 7.97 (t, J=7.6 Hz, 1H), 7.27 (d, J=7.88 Hz, 2H), 7.19 (d,J=7.84 Hz, 2H), 5.40 (dd, J=12.68, 5.36 Hz, 1H), 4.29 (s, 2H), 3.52-3.51(m, 4H), 3.40 (s, 2H), 2.97-2.83 (m, 2H), 2.67-2.63 (m, 1H), 2.32-2.28(m, 4H), 2.14-2.11 (m, 1H); LC MS: ES+ 471.6.

Example 121. Synthesis of3-[23-[[14-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-28-oxo-31,34-diazatricyclododeca-(2),1(21),7(23),22(24),25(31)-pentaen-34-yl]piperidine-2,6-dione(Compound 222)

Step 1: Synthesis of8-(4-(chloromethyl)benzyl)-1-oxa-8-azaspiro[4.5]decane: To the stirredsolution of 1-oxa-8-azaspiro[4.5]decane; hydrochloride 1 (1.0 g, 5.63mmol) in Acetone (10 mL) was added and stirred at 60° C. for 20 minutesfollowed by the addition of 1,4-bis(chloromethyl)benzene 2 (1.97 g,11.26 mmol, 1.39 mL).Resulting solution was further heated at sametemperature for 4 hr. After formation of desired pdt, as evidenced fromLCMS, volatiles were removed and re-dissolved in ethyl acetate. Organicportion was washed with eater/brine and separated, dried over sodiumsulfate and concentrated. Crude Residue was purified by columnchromatography to afford8-[[4-(chloromethyl)phenyl]methyl]-1-oxa-8-azaspiro[4.5]decane 3 (861mg, 2.95 mmol, 52.49% yield, 96% purity) as yellow gum. ¹H NMR (400 MHz,DMSO-d6) δ 7.36 (d, J=7.8 Hz, 2H), 7.28 (d, J=7.72 Hz, 2H), 4.73 (s,2H), 3.67 (t, J=Hz, 2H), 3.44 (s, 2H), 2.39 (br s, 2H), 2.31 (br s, 2H),1.85-1.78 (m, 2H), 1.62-1.59 (m, 2H), 1.53-1.51 (m, 4H);

Step 2: Synthesis of36-[(4-methoxyphenyl)methyl]-29-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-34,36-diazatricyclododeca-1(3),2(27),12(29),28(30),31(34)-pentaen-32-one:To a well degassed solution of8-[[4-(chloromethyl)phenyl]methyl]-1-oxa-8-azaspiro[4.5]decane 3 (400mg, 1.43 mmol) and26-[(4-methoxyphenyl)methyl]-15-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-25,26-diazatricyclododeca-6(8),7(18),13(15),19,21(25)-pentaen-22-one4 (1.19 g, 2.86 mmol) in ethanol (5.0 mL), Potassium phosphate tribasicanhydrous (910.37 mg, 4.29 mmol) was added followed by the additionTri-o-Tolyl phosphine (87.02 mg, 285.91 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (130.91 mg, 142.96umol). The resulting mixture was then heated at 90° C. for 12 hours.After completion of reaction (as monitored by LCMS), the reactionmixture was filtered through a bed of celite, washed with Ethyl acetate(100 mL). The combined filtrate was washed with water (3×20 mL) andbrine (2×15 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure. Crude mass was purified by column chromatography(silica, gradient:0-5% MeOH in DCM) to obtain36-[(4-methoxyphenyl)methyl]-29-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-34,36-diazatricyclododeca-1(3),2(27),12(29),28(30),31(34)-pentaen-32-one5 (300 mg, 505.94 umol, 35.39% yield, 90% purity) as yellow solid andstored in a round bottom glass at rt. LC MS: ES+ 534.2.

Step 3: Synthesis of21-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-26,27-diazatricyclododeca-(2),1(19),7(21),20(22),23(26)-pentaen-24-one:To the stirred solution of36-[(4-methoxyphenyl)methyl]-29-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-34,36-diazatricyclododeca-1(3),2(27),12(29),28(30),31(34)-pentaen-32-one5 (300 mg, 562.16 umol) in TFA (10 mL) Triflic acid (1.27 g, 8.43 mmol,740.07 uL) was added drop wise. The reaction mixture was stirred at 25°C. for 16 hours. After completion of reaction, the reaction mixture wasevaporated and quenched with saturated sodium bicarbonate solution andextracted with ethyl acetate (3×25 mL), washed with water followed bybrine. The organic part was dried over sodium sulphate and concentratedto afford crude21-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-26,27-diazatricyclododeca-(2),1(19),7(21),20(22),23(26)-pentaen-24-one6 (216 mg, 511.91 umol, 91.06% yield, 98% purity) as brown solid. LC MS:ES+ 414.1.

Step 4: Synthesis of3-[23-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-28-oxo-31,34-diazatricyclododeca-(2),1(21),7(23),22(24),25(31)-pentaen-34-yl]piperidine-2,6-dione:To a ice cooled solution of21-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-26,27-diazatricyclododeca-(2),1(19),7(21),20(22),23(26)-pentaen-24-one 6 (70 mg, 169.28 umol) in dry THF (3.0 mL),Sodiumhydride (in oil dispersion) 60% dispersion in mineral oil (67.71 mg,1.69 mmol, 60% purity) was added portion wise, maintaining the temp <5°C. Once the addition is over, the resultant mixture was stirred for 15minutes at RT. Then the reaction mixture was again cooled to 0° C. and3-bromopiperidine-2,6-dione 7 (162.52 mg, 846.41 umol) was added to itportion wise. After complete addition, resulting solution was heated at70° C. for 1 hour. After completion (evidenced from TLC), the reactionmixture was again cooled to 0° C. and quenched with ice cooled water (20mL). Aqueous part was extracted with ethyl acetate (3×50 mL). Combinedextracts was dried over anhydrous sodium sulfate and concentrated underreduced pressure. Crude mass was purified by Prep TLC (silica, gradient:80% Ethylacetate in DCM) to afford3-[23-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-28-oxo-31,34-diazatricyclododeca-(2),1(21),7(23),22(24),25(31)-pentaen-34-yl]piperidine-2,6-dioneCompound 222 (7.0 mg, 12.44 umol, 7.35% yield, 93.24% purity) as yellowsolid which was stored in a round bottomed flask at 5° C. inside arefrigerator. ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.24 (d, J=8.08Hz, 1H), 8.15-8.12 (m, 2H), 7.99-7.96 (m, 1H), 7.26-7.19 (m, 4H), 5.40(dd, J=12.44, 5.36 Hz, 1H), 4.30 (s, 2H), 3.67-3.64 (m, 2H), 3.34-3.32(m, 2H), 3.00-2.84 (m, 2H), 2.67-2.63 (m, 1H), 2.42-2.13 (m, 5H),1.82-1.81 (m, 2H), 1.60-1.59 (m, 2H), 1.50-1.49 (m, 4H); LC MS: ES+525.2.

Example 122. Synthesis of3-[6-[[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 223)

Step 1: Synthesis of 1,1-dimethyl-4-oxopiperidin-1-ium iodide: To thestirred solution of 1-methyl-piperidine-4-one 1 (2.3 g, 20.35 mmol) in15 ml of acetone was cooled to 0° C. and add 1.3 ml of Methyl iodideslowly into the reaction mixture and then it was stirred at ambienttemperature for 24 hours. The reaction mass was then concentrated andfiltered through sintered and then the solid compound was dried undervacuum to afford 1,1-dimethyl-piperidine-4-one 2 (4.0 g) as brown solid.

Step 2: Synthesis of 1-(1-cyclopropylcyclopropyl)piperidin-4-one: To thestirred solution of N-chloro-1-cyclopropyl-cyclopropanamine 3 (2.0 g,14.97 mmol) and 1-iodo-1,1-dimethyl-1$1{circumflex over( )}{5}-azinan-4-one 2 (3.82 g, 14.97 mmol) in Ethanol (50.0 mL) andPotassium carbonate-granular (2.48 g, 17.96 mmol, 1.08 mL) in solutionof Water (24.0 mL) was added and the reaction mixture was then heated at80° C. for 3 hours. Reaction mass was then cooled to room temperatureand then it was diluted with ethyl acetate and the layers wereseparated. It was dried over sodium sulfate and concentrated underreduced pressure at a very low temperature. Then again it was extractedwith dichloromethane and with a very little amount of water and thendried over sodium sulfate. The crude was then triturated with diethylether and then decanted part was concentrated under reduced pressure toafford 1-(1-cyclopropylcyclopropyl)piperidin-4-one 4 (2.2 g, 10.34 mmol,69.06% yield, 84.22% purity) as brown liquid and it was used for thenext step without purification. LC MS: ES+ 179.8. NOTE: All theconcentration processes were done in a very low temperature.

Step 3: Synthesis of tert-butylN-[[1-(1-cyclopropylcyclopropyl)-4-piperidyl]amino]carbamate: To thestirred solution of 1-(1-cyclopropylcyclopropyl)piperidin-4-one 4 (600.0mg, 3.35 mmol) in Acetic Acid (7.0 mL) was added tert-butylN-aminocarbamate (442.36 mg, 3.35 mmol) and then it was stirred at 25°C. for 2 hours. Sodium cyanoborohydride (252.41 mg, 4.02 mmol) was addedin portion wise manner. After the addition process was done it wasstirred at 25° C. for 16 hours. The reaction mass then concentratedunder reduced pressure and then 5(N) NaOH was added just to maintainpH-8 and extracted with dichloromethane. Organic layer was separated andthen it was dried over anhydrous sodium sulfate and then it wasconcentrated under reduced pressure to afford the crude material. Thecrude was then purified by column chromatography eluting 6-7% MeOH inDCM to afford tert-butylN-[[1-(1-cyclopropylcyclopropyl)-4-piperidyl]amino]carbamate 5 (650.0mg, 2.20 mmol, 65.74% yield, 100% purity) as brown sticky material. LCMS: ES+ 295.8.

Step 4: Synthesis of ethyl1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazole-4-carboxylate: Tothe stirred solution of tert-butylN-[[1-(1-cyclopropylcyclopropyl)-4-piperidyl]amino]carbamate 5 (620.0mg, 2.10 mmol) in Ethanol (24 mL) was added ethyl2-formyl-3-oxo-propanoate (302.48 mg, 2.10 mmol, 264.63 uL) and then 4MDioxane-HCl (12 mL) at 25° C. and then the reaction mass was stirred at75° C. for 5 hours. Reaction mass was then concentrated under reducedpressure and then it was extracted with ethyl acetate and the organiclayer was washed with saturated sodium bicarbonate solution and then itwas dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford the crude material. The crude was then purified bycolumn chromatography by eluting 5-7% MeOH in DCM to afford ethyl1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazole-4-carboxylate 6(550.0 mg, 1.60 mmol, 76.37% yield, 88.41% purity) as a white solid; LCMS: ES+ 303.9.

Step 5: Synthesis of[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methanol: Tothe stirred solution of ethyl1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazole-4-carboxylate 6(2.2 g, 7.25 mmol) in THF (35.0 mL) was added DIBAL (20.63 g, 36.26mmol, 29.42 mL, 25% purity) at −78° C. drop wise manner and then it wasstirred at −50 to −65° C. for 1 hour. Reaction mass was then dilutedwith ethyl acetate and poured into a conical containing ice and then toit Rochelle salt was added. It was stirred at ambient temperature for 1hour. Then the layers were separated and the organic fraction was driedover anhydrous sodium sulfate, concentrated under reduced pressure toafford[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methanol 7(1.8 g, 6.47 mmol, 89.16% yield, 93.88% purity) as brown solid. It wasused for the next step without purification; LC MS: ES+ 261.9.

Step 6: Synthesis of4-[4-(chloromethyl)pyrazol-1-yl]-1-(1-cyclopropylcyclopropyl)piperidine:N,N-Diisopropylethylamine (1.48 g, 11.48 mmol, 2.00 mL) was added bysyringe to a stirred solution of[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methanol 7(2.0 g, 7.65 mmol) in DCM (50.0 mL) at 0° C. under nitrogen, followed byMethanesulfonyl chloride, 98% (876.56 mg, 7.65 mmol, 592.27 uL) neat bysyringe and stirred the reaction mix at room temperature for overnight.The reaction was diluted with 100 ml DCM and cooled the reaction mixthen the reaction mix was washed with 2(N) HCl and with saturated NaHCO₃solution. The organics were isolated, dried over Na₂SO₄ and concentratedto afford the crude compound4-[4-(chloromethyl)pyrazol-1-yl]-1-(1-cyclopropylcyclopropyl)piperidine8 (1.7 g, 4.25 mmol, 55.58% yield, 70% purity) as light yellow gum; LCMS: ES+ 281.1.

Step 7: Synthesis of6-[[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of4-[4-(chloromethyl)pyrazol-1-yl]-1-(1-cyclopropylcyclopropyl)piperidine8 (800 mg, 2.86 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one9 (1.69 g, 5.72 mmol) in ethanol (2.0 mL) and Toluene (4.0 mL) was addedPotassium phosphate tribasic anhydrous (1.82 g, 8.58 mmol) and thereaction mass was degassed under nitrogen atmosphere over 10 minutes.Then Tri-o-Tolyl phosphine (174.05 mg, 571.82 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (261.81 mg, 285.91umol) was added to this reaction mass and the resultant reaction mixturewas heated 90° C. for overnight. Reaction mix was filtered throughsintered funnel using celite bed and the filtrate was diluted with ethylacetate, washed with water. The organic part was dried over Na₂SO₄,filtered and evaporated under reduced pressure. Crude material waspurified by combi-flash chromatography to get the pure compound6-[[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one10 (98 mg, 213.80 umol, 7.48% yield, 90% purity) as greenish solid. LCMS: ES+ 413.4.

Step 8: Synthesis of3-[6-[[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a ice cooled solution of6-[[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one10 (98 mg, 237.56 umol) in dry THF (5.0 mL), Sodium hydride (in oildispersion) 60% dispersion in mineral oil (91.03 mg, 2.38 mmol, 60%purity) was added portion wise, maintaining the temp <5° C. Once theaddition is over, the resultant mixture was stirred for 15 minutes atRT. Then the reaction mixture was again cooled to 0° C. and3-bromopiperidine-2,6-dione 11 (228.07 mg, 1.19 mmol) was added to itportion wise. After complete addition, resulting solution was heated at70° C. for 1 hour. After completion (evidenced from TLC), the reactionmixture was again cooled to 0° C. and quenched with ice cooled water (20mL). Aqueous part was extracted with ethyl acetate (3×50 mL). Combinedextracts was dried over anhydrous sodium sulfate and concentrated underreduced pressure. Crude mass was purified by Prep TLC (silica, gradient:80% Ethyl acetate in DCM) to afford3-[6-[[1-[1-(1-cyclopropylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 223 (17 mg, 30.67 umol, 12.91% yield, 94.46% purity) as yellowsolid which was stored in a round bottomed flask at 5° C. inside arefrigerator. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.28Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.56 (s, 1H),7.35 (d, J=7.32 Hz, 1H), 7.28 (s, 1H), 7.06 (d, J=7.24 Hz, 1H), 5.43(dd, J=12.72, 5.08 Hz, 1H), 4.17 (s, 2H), 4.01-3.99 (m, 1H), 2.99-2.86(m, 3H), 2.79-2.62 (m, 4H), 2.09-2.06 (m, 1H), 1.90-1.87 (m, 2H),1.72-1.69 (m, 2H), 1.24-1.23 (m, 1H), 0.30 (br s, 4H), 0.23 (br s, 2H),0.09 (br s, 2H); LC MS: ES+ 524.7.

Example 123. General Synthesis of Compound 224-Compound 231

Step 1: To a stirred solution of Amine 2 (1 eq) in dry grade acetone (15mL) was added Potassium carbonate, anhydrous, 99% (3 eq) at RT and theresultant reaction mixture was heated at 50° C. for 20 minutes.1,4-bis(chloromethyl)benzene (1) (1 eq) was then added to the reactionmixture and heating was continued for 3 hours. After completion ofreaction (monitored by TLC and LCMS), volatiles were removed undervacuum and the solid thus obtained was taken in Ethyl acetate (50 mL),washed with water (3×25 ml) and Brine (2×15 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure. Crude mass waspurified by column chromatography (silica, gradient: 10-30% Ethylacetate in Hexane) to afford (3) as colorless sticky solid which wasstored in a round bottomed flask at 5° C. inside a refrigerator.

Step 2: To a well degassed solution of (3) (1 eq) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(4) (2 eq) in Ethanol (2 mL)-Toluene (4 mL), Potassium phosphatetribasic, anhydrous, (3 eq) was added followed by the addition ofTri-o-Tolyl phosphine (0.2 eq) and Pd₂(dba)₃ (0.1 eq). The resultingmixture was then heated at 90° C. for 12 hours. After completion ofreaction (as monitored by LCMS), the reaction mixture was filteredthrough a bed of celite, washed with Ethyl acetate. The combinedfiltrate was then washed with water and brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. Crude mass waspurified by column chromatography (silica, gradient: 0-20% Ethyl acetatein DCM) to obtain (5) as yellow solid which was stored in a Tarsonplastic bottle at ambient temperature.

Step 3: To an ice cooled solution of (5) (1 eq) in dry THF (4 mL),Sodium hydride (60% dispersion in mineral oil) (10 eq) was added portionwise, maintaining the temp <5° C. Once the addition is over, theresultant mixture was stirred for 15 minutes at RT. Then the reactionmixture was again cooled to 0° C. and 3-bromopiperidine-2,6-dione (6) (5eq) was added to it portion wise. After complete addition, resultingsolution was heated at 70° C. for 1 hour. After completion (evidencedfrom TLC), the reaction mixture was again cooled to 0° C. and quenchedwith ice cooled water. Aqueous part was extracted with ethyl acetate.Combined extracts was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. Crude mass was purified by flashchromatography (silica, gradient: 2.5% MeOH in DCM) to afford an analogas yellow solid which was stored in a round bottomed flask at 5° C.inside a refrigerator.

Compound 224

(55 mg, 98.74 umol, 26.53% yield, 96.17% purity) as yellow solid. ¹H NMR(400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.28 (d, J=8.28 Hz, 1H), 8.07 (d,J=6.96 (Hz, 1H), 7.80 (t, J=7.76 Hz, 1H), 7.41 (d, J=7.28 Hz, 1H),7.24-7.21 (m, 4H), 7.10 (d, J=7.28 Hz, 1H), 5.44 (dd, J=12.72, 5.0 Hz,1H), 4.38 (s, 2H), 3.38 (br s, 2H), 2.99-2.90 (m, 1H), 2.8-2.62 (m, 3H),2.49-2.32 (br m, 4H), 2.1-2.07 (m, 1H), 1.34 (br, 9H), 1.26-1.23 (br m,4H); LC MS: ES+ 536.3.

Compound 225

(42.0 mg, 78.75 umol, 21.55% yield, 97.81% purity) as yellow solid. ¹HNMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.31 (d, J=8.16 Hz, 1H), 8.07(d, J=6.96 Hz, 1H), 7.80 (t, J=7.68 Hz, 1H), 7.40 (d, J=7.48 Hz, 1H),7.22-7.17 (m, 4H), 7.10 (d, J=7.28 Hz, 1H), 5.44 (dd, J=12.72, 5.36 Hz,1H), 4.37 (s, 2H), 3.34 (s, 2H), 2.98-2.90 (m, 1H), 2.76-2.62 (m, 2H),2.246 (br m, 4H), 2.10-2.07 (m, 1H), 1.528 (br s, 4H), 1.34-1.32 (m,8H); LC MS: ES+ 522.6.

Compound 226

(23.0 mg, 45.78 umol, 33.92% yield, 95.85% purity) as yellow solid. ¹HNMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.33 (d, J=8.16 Hz, 1H), 8.07(d, J=7.04 Hz, 1H), 7.80 (t, J=7.92 Hz, 1H), 7.40 (d, J=7.24 Hz, 1H),7.23 (m, 4H), 7.10 (d, J=7.32 Hz, 1H), 5.44-5.42 (m, 1H), 4.37-4.35 (brs, 4H), 3.63 (s, 2H), 2.98-2.88 (m, 3H), 2.80-2.49 (m, 5H), 2.21 (d,J=7.4 Hz, 1H), 2.10 (br, 1H); LC MS: ES+ 482.2.

Compound 227

(82 mg, 144.32 umol, 31.21% yield, 95.68% purity) as yellow solid. ¹HNMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.34 (d, J=8.2 Hz, 1H), 8.07 (d,J=7.0 Hz, 1H), 7.81 (t, J=7.84 Hz, 1H), 7.42 (d, J=7.4 Hz, 1H),7.27-7.10 (m, 10H), 5.44 (dd, J=12.6, 4.8 Hz, 1H), 4.39 (s, 2H), 3.36(br s, 2H), 2.98-2.92 (m, 3H), 2.79-2.62 (m, 3H), 2.32-2.08 (br m, 3H),1.90 (m, 4H), LC MS: ES+ 544.3.

Compound 228

(32.0 mg, 58.15 umol, 25.84% yield, 97.70% purity) as yellow solid. ¹HNMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.28 Hz, 1H), 8.07(d, J=7.08 Hz, 1H), 7.80 (t, J=7.68 Hz, 1H), 7.40 (d, J=7.16 Hz, 1H),7.21-7.18 (m, 4H), 7.10 (d, J=7.4 Hz, 1H), 5.45-5.42 (m, 1H), 4.37 (s,2H), 3.49 (m, 2H), 3.38 (br, 2H), 2.97-2.92 (m, 1H), 2.76-2.73 (m, 1H),2.69-2.62 (m, 1H), 2.49-2.32 (br, 2H), 2.21-2.07 (br m, 3H), 1.52 (br,2H), 1.39 (br m, 2H), 1.33-1.23 (m, 6H); LC MS: ES+ 538.5.

Compound 229

(60.0 mg, 122.03 umol, 23.09% yield, 99.57% purity) as yellow solid. ¹HNMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.31 (d, J=8.24 Hz, 1H), 8.06(d, J=6.92 Hz, 1H), 7.79 (t, J=7.64 Hz, 1H), 7.38 (d, J=7.32 Hz, 1H),7.22 (d, J=7.88 Hz, 2H), 7.13-7.07 (m, 5H), 6.66 (d, J=8.08 Hz, 2H),6.57 (t, J=7.16 Hz, 1H), 5.43 (dd, J=12.72, 4.88 Hz, 1H), 4.47 (s, 2H),4.35 (s, 2H), 2.94 (s, 3H), 2.93-2.91 (m, 1H), 2.79-2.62 (m, 2H),2.09-2.06 (m, 1H); LC MS: ES+ 490.2.

Compound 230

(65 mg, 133.77 umol, 38.71% yield, 99.10% purity) as yellow solid. ¹HNMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.30 (d, J=8.32 Hz, 1H), 8.07(d, J=6.96 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 7.39 (d, J=7.36 Hz, 1H),7.20 (d, J=7.8 Hz, 2H), 7.13-7.09 (m, 3H), 5.44 (dd, J=12.68, 4.72 Hz,1H), 4.55 (s, 4H), 4.36 (s, 2H), 3.39 (s, 2H), 3.20 (s, 4H), 2.98-2.90(m, 1H), 2.79-2.62 (m, 2H), 2.10-2.07 (m, 1H); LC MS: ES+ 482.2.

Compound 231

(44.0 mg, 85.60 umol, 15.04% yield, 96.80% purity) as yellow solid. ¹HNMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.32 (d, J=8.16 Hz, 1H), 8.07(d, J=6.92 Hz, 1H), 7.80 (t, J=7.62 Hz, 1H), 7.40 (d, J=7.32 Hz, 1H),7.23 (d, J=7.88 Hz, 2H), 7.17 (d, J=7.6 Hz, 2H), 7.10 (d, J=7.2 Hz, 1H),5.46-5.42 (m, 1H), 4.37 (s, 2H), 3.50-3.48 (m, 2H), 3.34 (s, 2H),2.95-2.91 (m, 1H), 2.77-2.73 (m, 1H), 2.66-2.59 (m, 3H), 2.10-2.09 (m,1H), 1.57 (t, J=10.62 Hz, 2H), 0.98 (d, J=6.16 Hz, 6H); LC MS: ES+498.5.

Example 124. Synthesis of3-(6-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 232)

Step 1: Synthesis of3-(6-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dioneCompound 232 following general reductive amination procedure. (90.0 mg,162.66 umol, 12.26% yield, 95.0% purity) as yellow solid. ¹H NMR (400MHz, DMSO-d6) δ 11.11 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.07 (d, J=7.0Hz, 1H), 7.80 (t, J=7.64 Hz, 1H), 7.40 (d, J=7.24 Hz, 1H), 7.25-7.17 (m,4H), 7.10 (d, J=7.28 Hz, 1H), 5.44-5.41 (m, 1H), 4.37 (s, 2H), 4.00 (brs, 1H), 2.95-2.93 (m, 1H), 2.79-2.62 (m, 4H), 2.10-2.09 (m, 1H),1.77-1.76 (m, 2H), 1.60-1.57 (m, 2H), 1.23-1.14 (m, 4H), 0.99 (s, 6H);LC MS: ES+ 526.2.

Example 125. Synthesis of3-(6-((1-(1-((1-fluorocyclopropyl)methyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 106)

Step 1: Synthesis of3-(6-((1-(1-((1-fluorocyclopropyl)methyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione,Compound 106 following general reductive amination procedure. (100.0 mg,184.69 umol, 70.18% yield, 97.81% purity) as yellow solid. ¹H NMR (400MHz, DMSO-d6) δ 11.10 (s, 1H), 8.38 (d, J=8.24 Hz, 1H), 8.08 (d, J=6.92Hz, 1H), 7.82 (t, J=7.62 Hz, 1H), 7.73 (s, 1H), 7.34 (d, J=7.32 Hz, 1H),7.30 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.84, 5.24 Hz, 1H),4.20 (s, 2H), 2.95-2.90 (m, 1H), 2.78-2.72 (m, 1H), 2.67-2.63 (m, 5H),2.33-2.29 (m, 4H), 2.10-2.07 (m, 1H), 1.83-1.78 (m, 2H), 1.29 (s, 3H),0.97-0.87 (m, 2H), 0.62-0.60 (m, 2H); LC MS: ES+ 530.2.

Example 126. Synthesis of3-(6-((1-(4-methyl-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 105)

Step 1: Synthesis of3-(6-((1-(4-methyl-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione,Compound 105 following general reductive amination procedure. (90.0 mg,150.46 umol, 57.17% yield, 96.90% purity) as yellow solid. ¹H NMR (400MHz, DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=7.68 Hz, 1H), 8.08 (d, J=6.36Hz, 1H), 7.83-7.81 (m, 1H), 7.71 (s, 1H), 7.36-7.30 (m, 2H), 7.07 (d,J=6.04 Hz, 1H), 5.44-5.42 (m, 1H), 4.19 (s, 2H), 3.03-2.91 (m, 1H),2.77-2.62 (m, 2H), 2.50-2.48 (m, 2H), 2.40 (s, 2H), 2.30-2.29 (m, 2H),2.15-2.07 (m, 3H), 1.78-1.77 (m, 2H), 1.28 (s, 3H), 0.92 (br s, 2H),0.66 (br s, 2H); LC MS: ES+ 580.3.

Example 127. Synthesis of3-(6-((1-(4-methyl-14(1-methylcyclobutyl)sulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 233)

Step 1: Synthesis of3-(6-((1-(4-methyl-14(1-methylcyclobutyl)sulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To the stirred solution of3-[6-[[1-(1-chloro-4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione1 (80.0 mg, 161.95 umol) in DCM (1 mL) was added Triethylamine (49.16mg, 485.85 umol, 67.72 uL) in cold condition followed by the addition1-methylcyclobutanesulfonyl chloride 2 (27.31 mg, 161.95 umol, 20.23 uL)and the reaction was continued at room temperature for 16 hours. Thereaction mixture was diluted with ethyl acetate, washed with sodiumbicarbonate solution, water and the organic fraction was separated. Itwas dried over anhydrous sodium sulphate and evaporated under reducedpressure to obtain the crude which was purified by preparative TLC platemethod developing the plate in 3% MeOH-DCM to afford3-[6-[[1-[4-methyl-1-(1-methylcyclobutyl)sulfonyl-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 233 (18.0 mg, 29.90 umol, 18.47% yield, 97.97% purity) asyellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.08Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.82 (t, J=7.74 Hz, 1H), 7.76 (s, 1H),7.35 (s, 2H), 7.07 (d, J=7.24 Hz, 1H), 5.43-5.41 (m, 1H), 4.20 (s, 2H),3.38-3.32 (m, 2H), 3.03-2.94 (m, 3H), 2.70-2.50 (m, 4H), 2.36-2.32 (m,3H), 2.08-2.07 (m, 1H), 1.95-1.93 (m, 1H), 1.80-1.76 (m, 4H), 1.38 (s,3H), 1.34 (s, 3H); LC MS: ES+ 590.5.

Example 128. Synthesis of3-[6-[[1-[1-[(1-methylcyclopropyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 234) and3-[6-[[1-[1-[(1-methylcyclopropyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 235)

Step 1: Chiral separation of3-[6-[[1-[1-[(1-methylcyclopropyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 64 (1.5 g, 2.93 mmol) was separated into enantiomers by Normalphase Chiral Prep HPLC to afford3-[6-[[1-[1-[(1-methylcyclopropyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 234 (600.0 mg, 39.94% yield, % ee 100, first eluting fraction)as yellow solid and3-[6-[[1-[1-[(1-methylcyclopropyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 235 (550.0 mg, 36.53% yield, % ee 100, second eluting fraction)as yellow solid.

Example 129. Synthesis of3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 236) and3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 237)

Step 1: Chiral separation of3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(1.8 g, 3.42 mmol) was separated to the enantiomers by Normal phaseChiral Prep HPLC to afford3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 236 (840.0 mg, 46.51% yield, eluted as first fraction, % ee 99)and3-[6-[[1-[1-[(1-methylcyclobutyl)methyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 237 (650.0 mg, 35.82% yield, as second fraction, % ee 99) asyellow solids.

Example 130. Synthesis of3-[6-[[1-[4-methyl-1-(2-oxabicyclo[2.1.1]hexane-4-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 238) and3-[6-[[1-[4-methyl-1-(2-oxabicyclo[2.1.1]hexane-4-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 239)

Step 1: Chiral separation: 250 mg of3-(6-{1-[4-Methyl-1-(2-oxa-bicyclo[2.1.1]hexane-4-carbonyl)-piperidin-4-yl]-1H-pyrazol-4-ylmethyl}-2-oxo-2H-benzo[cd]indol-1-yl)-piperidine-2,6-dioneCompound 71 was separated into enantiomers by chiral SFC method toafford3-[6-[[1-[4-methyl-1-(2-oxabicyclo[2.1.1]hexane-4-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 238 (85 mg, 24.47% yield, eluted as first fraction, % ee 100)and3-[6-[[1-[4-methyl-1-(2-oxabicyclo[2.1.1]hexane-4-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 239 (92 mg, 26.56% yield, eluted as second fraction, % ee 95)as yellow solids.

Example 131. Synthesis of3-(2-oxo-6-((1-(1-(2,2,3,3-tetramethylcyclopropyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 240)

Step-1: Synthesis of6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-onehydrochloride: To a stirred solution of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate1 (200 mg, 462.41 umol) in Dioxane (2 mL) was added 4M Dioxane-HCl(462.41 umol, 5 mL) at 0° C. It was stirred at RT for 2 hours. It wasconcentrated under reduced pressure to afford6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 2 (160mg, 430.65 umol, 93.13% yield, 99.28% purity) as yellow solid; LC MS:ES+ 333.2.

Step-2: Synthesis of6-((1-(1-(2,2,3,3-tetramethylcyclopropyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one:To a stirred solution of6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 2 (300mg, 902.53 umol) in DMF (1 mL) was added Potassium carbonate (374.22 mg,2.71 mmol, 163.41 uL) and followed by3-bromo-1,1,2,2-tetramethyl-cyclopropane 3 (191.79 mg, 1.08 mmol) at 0°C. and Potassium iodide(cat.). It was heated at 60° C. for 16 hours. Itwas diluted with ethyl acetate, washed with water, brine, dried oversodium sulfate and concentrated under reduced pressure. It was cooled toRT, diluted with ethyl acetate, washed with ice cold water, brine, driedover sodium sulfate and concentrated under reduced pressure. It waspurified by preparative TLC (1% methanol in ethyl acetate) to afford6-[[1-[1-(2,2,3,3-tetramethylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one4 (15 mg, 28.00 umol, 3.10% yield, 80% purity) as yellow solid; LC MS:ES+ 428.3.

Step-3: Synthesis of3-(2-oxo-6-((1-(1-(2,2,3,3-tetramethylcyclopropyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To a stirred solution of6-[[1-[1-(2,2,3,3-tetramethylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one4 (50 mg, 116.67 umol) in DMF (1 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (2.68 mg, 116.67 umol) at 0°C. It was stirred at RT for 10 minutes. 3-bromopiperidine-2,6-dione(44.80 mg, 233.34 umol) was added to the reaction mixture portion wiseat 0° C. After stirring at 0° C. for 5 minutes it was heated at 70° C.for 1 hour. It was cooled to RT, diluted with ice cold water, extractedwith ethyl acetate, washed with brine, dried over sodium sulfate andconcentrated under reduced pressure. It was purified by preparative TLC(3% methanol in dichloromethane) to afford3-[2-oxo-6-[[1-[1-(2,2,3,3-tetramethylcyclopropyl)-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 240 (18 mg, 33.00 umol, 28.29% yield, 98.94% purity) as yellowsolid. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.04 Hz,1H), 8.08 (d, J=8.24 Hz, 1H), 7.83-7.81 (m, 1H), 7.55 (s, 1H), 7.35 (d,J=6.36 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.45-5.42 (m,1H), 5.02 (br s, 1H), 4.17 (s, 2H), 3.95-3.93 (m, 1H), 3.03-2.94 (m,3H), 2.76-2.49 (m, 2H), 2.32-2.10 (m, 3H), 1.89-1.76 (m, 7H), 1.63 (s,3H), 1.08 (s, 6H); LC MS: ES+ 540.6.

Example 132. Synthesis of4-{4-[1-(2,6-Dioxo-piperidin-3-yl)-2-oxo-1,2-dihydro-benzo[cd]indole-6-carbonyl]-pyrazol-1-yl}-4-methyl-piperidine-1-carboxylicacid tert-butyl ester (Compound 241)

Step-1: Synthesis of 6-Bromo-1H-benzo[cd]indol-2-one: To the stirredsuspension of 1H-benzo[cd]indol-2-one 1 (20 g, 118.22 mmol) in CHCl3(250 mL) was added molecular bromine (28.34 g, 177.33 mmol, 9.08 mL) atcold condition drop wise and the reaction was continued at roomtemperature for 48 hours. After completion of the reaction (monitored byTLC and LCMS) the reaction mixture was poured into saturated aq.solution of sodium thiosulphate and the yellow solid formed was filteredthrough sintered funnel, washed with water, pentane and aziotroped withtoluene to afford 6-bromo-1H-benzo[cd]indol-2-one 2 (23.5 g, 92.83 mmol,78.53% yield, 98% purity) as yellow solid; LCMS: ES+ 250.1.

Step-2: Synthesis of4-{4-[Hydroxy-(2-oxo-1,2-dihydro-benzo[cd]indol-6-yl)-methyl]-pyrazol-1-yl}-4-methyl-piperidine-1-carboxylicacid tert-butyl ester: To the stirred solution of6-bromo-1H-benzo[cd]indol-2-one 2 (510 mg, 2.06 mmol) in THF (7 mL) wasadded Butyllithium (2.15 M, 2.10 mL) at −78° C. and after the additionwas complete the temperature was allowed to increase to −40° C. and thereaction mixture was stirred at the same temperature for 30 minutesfollowed by the addition of tert-butyl4-(4-formylpyrazol-1-yl)-4-methyl-piperidine-1-carboxylate 3 (603.10 mg,2.06 mmol) in THF (7 mL) at −78° C. and then the reaction mixture wasallowed to warm to room temperature and was continued for 16 hours.Reaction mixture was quenched with ammonium chloride solution, dilutedwith ethyl acetate, washed with water and the organic fraction wasseparated. It was then dried over anhydrous sodium sulphate andevaporated under reduced pressure to obtain the crude compound which waspurified by flash chromatography using 0-5% MeOH-DCM to affordtert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methyl-piperidine-1-carboxylate4 (210.0 mg, 426.32 umol, 20.74% yield, 93.9% purity) as brown solid;LCMS: ES+ 445.1 (mass without the OH group).

Step-3: Synthesis of4-Methyl-4-[4-(2-oxo-1,2-dihydro-benzo[cd]indole-6-carbonyl)-pyrazol-1-yl]-piperidine-1-carboxylicacid tert-butyl ester: To the stirred solution of tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-methyl-piperidine-1-carboxylate4 (210.0 mg, 454.02 umol) in DCM (4.0 mL) was added Manganese dioxide(394.71 mg, 4.54 mmol) and the reaction mixture was stirred at roomtemperature for 16 hours. After completion of the reaction (monitored byTLC) the reaction mixture was filtered over celite bed, washed withethyl acetate and the filtrate was evaporated under reduced pressure toobtain the crude compound which was purified by flash chromatographyusing 0-5% MeOH-DCM to afford tert-butyl4-methyl-4-[4-(2-oxo-1H-benzo[cd]indole-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylate 5 (135.0 mg, 284.64umol, 62.69% yield, 97.1% purity) as pale yellow solid; LCMS: ES+ 461.4.

Step-4: Synthesis of4-{4-[1-(2,6-Dioxo-piperidin-3-yl)-2-oxo-1,2-dihydro-benzocarbonyl]-pyrazol-1-yl}-4-methyl-piperidine-1-carboxylic acid tert-butylester: To the stirred solution of tert-butyl4-methyl-4-[4-(2-oxo-1H-benzo[cd]indole-6-carbonyl)pyrazol-1-yl]piperidine-1-carboxylate5 (135.0 mg, 293.14 umol) in DMF (1 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (29.31 mg, 732.86 umol, 60%purity) at cold condition and the reaction mixture was heated at 70° C.for 1 hour followed by the addition of 3-bromopiperidine-2,6-dione(56.29 mg, 293.14 umol) and the reaction was heated at 70° C. for 4hours with further top up of 3-bromopiperidine-2,6-dione 6 (56.29 mg,293.14 umol). The reaction was continued at 70° C. for 16 hours. Thereaction mixture was diluted with ethyl acetate, washed with water andthe organic fraction was separated. It was then dried over anhydroussodium sulphate and evaporated under reduced pressure to obtain thecrude which was purified by preparative TLC plate method developing theplate in 40% ethyl acetate-DCM to afford tert-butyl4-[4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indole-6-carbonyl]pyrazol-1-yl]-4-methyl-piperidine-1-carboxylateCompound 241 (10.0 mg, 17.38 umol, 5.93% yield, 99.34% purity) as lightyellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.59 (d, J=8.36Hz, 1H), 8.51 (s, 1H), 8.18 (d, J=6.88 Hz, 1H), 8.07 (d, J=7.68 Hz, 1H),8.03 (s, 1H), 7.92 (t, J=7.7 Hz, 1H), 7.27 (d, J=7.56 Hz, 1H), 5.53 (dd,J=12.64, 4.32 Hz, 1H), 3.52-3.48 (m, 2H), 3.20-3.19 (m, 2H), 2.97-2.93(m, 2H), 2.83-2.76 (m, 1H), 2.70-2.67 (m, 1H), 2.40-2.27 (m, 2H),2.16-2.15 (m, 1H), 1.87-1.84 (m, 2H), 1.47 (s, 3H), 1.39 (s, 9H); LC MS:ES+ 572.5.

Example 133. Synthesis of3-{2-Oxo-6-[1-(1-spiro[3.4]oct-5-yl-piperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}-piperidine-2,6-dione(Compound 242) and3-{2-Oxo-6-[1-(1-spiro[3.4]oct-5-yl-piperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}-piperidine-2,6-dione(Compound 243)

Step-1: Synthesis of6-(1-Piperidin-4-yl-1H-pyrazol-4-ylmethyl)-1H-benzo[cd]indol-2-one, HClsalt: To a stirred solution of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate1 (200 mg, 462.41 umol) in Dioxane (2 mL) was added 4M Dioxane-HCl(462.41 umol, 5 mL) at 0° C. It was stirred at RT for 2 h. It wasconcentrated under reduced pressure to afford6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 2 (160mg, 430.65 umol, 93.13% yield, 99.28% purity) as yellow solid. LCMS: ES+333.2.

Step-2: Synthesis of6-[1-(1-Spiro[3.4]oct-5-yl-piperidin-4-yl)-1H-pyrazol-4-ylmethyl]-1H-benzo[cd]indol-2-one:To a stirred solution of6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one2 (200 mg, 542.21 umol) in THF (5 mL) was added Triethylamine (109.73mg, 1.08 mmol, 151.15 uL) followed by the addition ofspiro[3.4]octan-7-one 3 (67.33 mg, 542.21 umol), Dibutyltindichloride(197.70 mg, 650.65 umol, 145.37 uL) and Phenylsilane (58.67 mg, 542.21umol, 66.83 uL). The reaction mixture was then stirred at 90° C. for 16hours. After completion of the reaction (monitored by LCMS) the reactionmixture was cooled to RT, diluted with ethyl acetate, washed with water,brine dried over sodium sulfate and concentrated under reduced pressure.It was purified by combi flash eluting at 1% methanol in dichloromethaneto afford6-[[1-(1-spiro[3.4]octan-7-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one4 (175 mg, 378.18 umol, 69.75% yield, 95.21% purity) as yellow solid.LCMS: ES+ 440.9

Step-3: Chiral separation of6-[1-(1-Spiro[3.4]oct-5-yl-piperidin-4-yl)-1H-pyrazol-4-ylmethyl]-1H-benzo[cd]indol-2-one(4a) and6-[1-(1-Spiro[3.4]oct-5-yl-piperidin-4-yl)-1H-pyrazol-4-ylmethyl]-1H-benzo[cd]indol-2-one(4b):6-[[1-(1-spiro[3.4]octan-7-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one4 (175 mg, 397.20 umol) was submitted to SFC for chiral separation.Chiral isomers were separated by SFC to afford6-[[1-[1-[spiro[3.4]octan-7-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one4b (70 mg, 158.88 umol, 40.00% yield, 100% purity) (Peak 1) as yellowsolid LCMS: ES+ 441.6 and6-[[1-[1-[spiro[3.4]octan-7-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one4a (70 mg, 155.39 umol, 39.12% yield, 97.80% purity) (Peak 2) as yellowsolid. LCMS: ES+ 441.6.

Step-4: Synthesis of3-{2-Oxo-6-[1-(1-spiro[3.4]oct-5-yl-piperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}-piperidine-2,6-dioneand3-{2-Oxo-6-[1-(1-spiro[3.4]oct-5-yl-piperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}-piperidine-2,6-dione:To a stirred solution of6-[[1-[1-[spiro[3.4]octan-7-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one4a (65.00 mg, 147.53 umol) in THF (7 mL) was added Sodium hydride (inoil dispersion) 60% dispersion in mineral oil (56.53 mg, 1.48 mmol, 60%purity) portion wise at 0° C. It was stirred at RT for 10 minutes.3-bromopiperidine-2,6-dione 5 (141.64 mg, 737.67 umol) was added to thereaction mixture at RT portion wise. It was heated at 70° C. for 1 hour.It was cooled to RT, diluted with ethyl acetate, poured to ice coldwater, separated organic part, washed with water, brine and dried oversodium sulfate. It was evaporated under reduced pressure. It waspurified by preparative TLC (5% Methanol in Ethyl acetate in DCM) toafford3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-7-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 242 (28.0 mg, 46.78 umol, 31.70% yield, 92.16% purity) asyellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (d, J=8.24Hz, 1H), 8.08 (d, J=7.00 Hz, 1H), 7.82 (t, J=7.64 Hz, 1H), 7.57 (s, 1H),7.34 (d, J=7.28 Hz, 1H), 7.28 (s, 1H), 7.06 (d, J=7.28 Hz, 1H), 5.43(dd, J=12.68, 5.04 Hz, 1H), 4.17 (s, 2H), 3.99-3.97 (m, 1H), 2.92-2.90(m, 3H), 2.82-2.62 (m, 2H), 2.10-2.07 (m, 1H), 1.94-1.72 (m, 15H),1.60-1.57 (m, 2H), 1.41-1.35 (m, 2H); LC MS: ES+ 552.72.

To a stirred solution of6-[[1-[1-[spiro[3.4]octan-7-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one4b (80.00 mg, 181.58 umol) in THF (5 mL) was added Sodium hydride (inoil dispersion) 60% dispersion in mineral oil (66.65 mg, 1.74 mmol, 0.6purity) portion wise at 0° C. It was stirred at RT for 10 minutes.3-bromopiperidine-2,6-dione 5 (174.33 mg, 907.90 umol) was added to thereaction mixture at RT portion wise. It was heated at 70° C. for 1 h. Itwas cooled to RT, diluted with ethyl acetate, poured to ice cold water,separated organic part, washed with water, brine and dried over sodiumsulfate. It was evaporated under reduced pressure. It was diethyl etherto afford3-[2-oxo-6-[[1-[1-[spiro[3.4]octan-7-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 243 (21.5 mg, 37.04 umol, 20.40% yield, 95.05% purity) as lightgreen solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.37 (d, J=8.12Hz, 1H), 8.08 (d, J=6.92 Hz, 1H), 7.82 (t, J=7.56 Hz, 1H), 7.57 (s, 1H),7.34 (d, J=6.52 Hz, 1H), 7.28 (s, 1H), 7.06 (d, J=7.36 Hz, 1H),5.44-5.41 (m, 1H), 4.17 (s, 2H), 3.99-3.97 (m, 1H), 2.91-2.49 (m, 4H),2.09-1.77 (m, 16H), 1.67-1.57 (m, 2H), 1.41-1.38 (m, 2H); LC MS: ES+552.3.

Example 134. Synthesis of3-{2-Oxo-6-[1-(1-spiro[3.3]hept-1-yl-piperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}-piperidine-2,6-dione(Compound 244) and3-{2-Oxo-6-[1-(1-spiro[3.3]hept-1-yl-piperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}-piperidine-2,6-dione(Compound 245)

Step-1: Synthesis of6-(1-Piperidin-4-yl-1H-pyrazol-4-ylmethyl)-1H-benzo[cd]indol-2-one, HClsalt: To a stirred solution of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate1 (500 mg, 1.16 mmol) in Dioxane (5 mL) was added 4M Dioxane-HCl (1.16mmol, 5 mL) at 0° C. It was stirred at RT for 3 hours. It wasconcentrated under reduced pressure to afford6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one 2 (405mg, 1.05 mmol, 91.18% yield, 96% purity) as yellow solid. LCMS: ES+333.4.

Step-2: Synthesis of6-[1-(1-Spiro[3.3]hept-1-yl-piperidin-4-yl)-1H-pyrazol-4-ylmethyl]-1H-benzo[cd]indol-2-one:To a stirred solution of6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one2 (330 mg, 894.65 umol) in THF (5 mL) was added Triethylamine (181.06mg, 1.79 mmol, 249.39 uL) followed by the addition ofspiro[3.3]heptan-3-one 3 (98.55 mg, 894.65 umol), Dibutyltindichloride(326.21 mg, 1.07 mmol, 239.86 uL) and Phenylsilane (96.81 mg, 894.65umol, 110.26 uL). The reaction mixture was then stirred at 90° C. for 16hours. It was cooled to RT, diluted with ethyl acetate, washed withwater, brine dried over sodium sulfate and concentrated under reducedpressure. It was purified by combiflash eluting at 1% methanol indichloromethane to afford6-[[1-(1-spiro[3.3]heptan-3-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one4 (225 mg, 496.68 umol, 55.52% yield, 94.16% purity) as yellow solid,LCMS: ES+ 427.1.

Step-3: Chiral separation of6-[1-(1-Spiro[3.3]hept-1-yl-piperidin-4-yl)-1H-pyrazol-4-ylmethyl]-1H-benzo[cd]indol-2-one(4a) and6-[1-(1-Spiro[3.3]hept-1-yl-piperidin-4-yl)-1H-pyrazol-4-ylmethyl]-1H-benzo[cd]indol-2-one(4b):6-[[1-(1-spiro[3.3]heptan-3-yl-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one4 (225 mg, 527.49 umol) was submitted for chiral separation by SFC.Chiral isomers were separated by SFC to afford6-[[1-[1-[spiro[3.3]heptan-3-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(4b) (85 mg, 199.27 umol, 37.78% yield, 100% purity) (peak 1) as lightyellow solid LCMS: ES+ 427.0 and6-[[1-[1-[spiro[3.3]heptan-3-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(4a) (105 mg, 237.35 umol, 45.00% yield, 96.42% purity) (peak 2) aslight yellow solid; LCMS: ES+ 427.0.

Step-4: Synthesis of3-{2-Oxo-6-[1-(1-spiro[3.3]hept-1-yl-piperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}-piperidine-2,6-dioneand3-{2-Oxo-6-[1-(1-spiro[3.3]hept-1-yl-piperidin-4-yl)-1H-pyrazol-4-ylmethyl]-2H-benzo[cd]indol-1-yl}-piperidine-2,6-dione:To the stirred solution of6-[[1-[1-[spiro[3.3]heptan-3-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one4a (80.00 mg, 187.55 umol) in THF (15 mL) was added Sodium hydride (inoil dispersion) 60% dispersion in mineral oil (75.73 mg, 1.98 mmol, 60%purity) at cold condition and the reaction mixture was stirred at roomtemperature for 10 minutes followed by the addition of3-bromopiperidine-2,6-dione 5 (180.06 mg, 937.75 umol) portionwise. Itwas then stirred at room temperature for 10 minutes and heated at 80° C.for 30 minutes. TLC was checked which showed almost complete consumptionof the starting material and formation of the desired spot. The reactionmixture was diluted with ethyl acetate, washed with cold water and theorganic fraction was separated. It was then dried over anhydrous sodiumsulphate and evaporated under reduced pressure to obtain the crude whichwas purified by preparative TLC plate method developing the plate in 95%ethyl acetate-DCM to afford3-[2-oxo-6-[[1-[1-[spiro[3.3]heptan-3-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 244 (42.0 mg, 74.21 umol, 39.57% yield, 95% purity) as yellowsolid. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.4 Hz,1H), 8.08 (d, J=7.00 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.35(d, J=Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 5.44-5.41 (m, 1H),4.18 (s, 2H), 4.03 (br s, 1H), 2.99-2.91 (m, 2H), 2.77-2.62 (m, 3H),2.40-2.36 (m, 1H), 2.24-2.20 (m, 1H), 2.09-2.07 (m, 1H), 1.96-1.72 (m,12H), 1.57-1.55 (m, 1H), 1.45-1.42 (m, 1H); LC MS: ES+ 538.3. To astirred solution of6-[[1-[1-[spiro[3.3]heptan-3-yl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one4b (100.00 mg, 234.44 umol) in THF (4 mL) was added Sodium hydride (inoil dispersion) 60% dispersion in mineral oil (89.83 mg, 2.34 mmol, 0.6purity) at 0° C. It was stirred at RT for 10 minutes.3-bromopiperidine-2,6-dione 5 (225.07 mg, 1.17 mmol) was added portionwise. It was stirred at RT for 10 minutes. It was heated at 80° C. for 1hour. It was cooled to RT, diluted with ethyl acetate, poured into icecold water, separated organic part, washed with brine, dried over sodiumsulfate and concentrated under reduced pressure. It was purified bypreparative TLC (80% ethyl acetate in dichloromethane) to afford3-[2-oxo-6-[[1-[1-[spiro[3.3]heptan-3-yl]-4-piperidyl]pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 245 (48.0 mg, 84.81 umol, 36.18% yield, 95% purity) as yellowsolid. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.38 (d, J=8.2 Hz,1H), 8.08 (d, J=6.96 Hz, 1H), 7.83 (t, J=7.64 Hz, 1H), 7.59 (s, 1H),7.35 (d, J=7.32 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43(dd, J=12.76, 5.16 Hz, 1H), 4.18 (s, 2H), 4.03-4.01 (m, 1H), 2.99-2.94(m, 2H), 2.77-2.62 (m, 3H), 2.39-2.36 (m, 1H), 2.24-2.20 (m, 1H),2.09-2.06 (m, 1H), 1.95-1.65 (m, 13H), 1.57-1.55 (m, 1H), 1.45-1.40 (m,1H); LC MS: ES+ 538.3.

Example 135. Synthesis of3-(6-((4-(4-(1-methylcyclobutane-1-carbonyl)piperazin-1-yl)-1H-pyrazol-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 246)

Step-1: Synthesis of tert-butyl4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)piperazine-1-carboxylate:To a stirred solution of 4-iodo-1-tetrahydropyran-2-yl-pyrazole 2 (5.3g, 19.06 mmol) and tert-butyl piperazine-1-carboxylate 1 (3.55 g, 19.06mmol) in DMSO (30 mL) was added Cesium carbonate (15.52 g, 47.65 mmol)Reaction mixture was degassed with argon for 10 min. To the reactionmixture, Copper (I) iodide (1.09 g, 5.72 mmol, 193.76 uL) and2-acetylcyclohexanone (801.49 mg, 5.72 mmol, 756.12 uL) were added andagain degassed for 5 min. Reaction mixture was then heated at 110° C.for 18 hours. The reaction mixture was diluted with ethyl acetate andwater, layers were separated and organic layer was washed with water,brine, dried over Na₂SO₄ and concentrated under reduced pressure to getcrude mass which was purified by column chromatography using 40-50%EtOAc-Hexane as eluent to afford tert-butyl4-(1-tetrahydropyran-2-ylpyrazol-4-yl)piperazine-1-carboxylate 3 (1 g,2.69 mmol, 14.14% yield, 90.66% purity) as light black gum. LC MS: ES+337.5.

Step-2: Synthesis of 1-(1H-pyrazol-4-yl)piperazine hydrochloride: To astirred solution of tert-butyl4-(1-tetrahydropyran-2-ylpyrazol-4-yl)piperazine-1-carboxylate 3 (1 g,2.97 mmol) in 4M HCl in Dioxane (10 mL) and cooled the reaction mixtureto 0° C. followed by drop wise addition of 4M HCl in Dioxane (10 mL),stirred the reaction mixture for 3 hour at RT. LCMS showed product mass,the reaction mixture was concentrated under reduced pressure and washedwith Ether, dried to afford 1-(1H-pyrazol-4-yl)piperazine hydrochloride4 (450 mg, 2.27 mmol, 76.23% yield, 95% purity) as a white gum. LC MSwas not responded well.

Step-3: Synthesis of(4-(1H-pyrazol-4-yl)piperazin-1-yl)(1-methylcyclobutyl)methanone: To astirred solution of 1-(1H-pyrazol-4-yl)piperazine; hydrochloride 4 (500mg, 2.65 mmol) in DMF (8 mL) was added 1-methylcyclobutanecarboxylicacid 5 (302.51 mg, 2.65 mmol, 270.10 uL) followed by HATU (1.51 g, 3.98mmol) and the reaction mixture was cooled to 0° C. was added DIPEA (1.37g, 10.60 mmol, 1.85 mL), the reaction mixture was allowed to stirred atRT for overnight. Reaction mixture was diluted with water and wasextracted with ethyl acetate, organic layer was washed with saturatedsodium bicarbonate solution (3×) followed by water and brine, dried oversodium sulphate and concentrated under reduced pressure to get the crudeproduct. The crude product thus obtained was purified by columnchromatography eluting with 25% of EtOAc in Hexane to afford(1-methylcyclobutyl)-[4-(1H-pyrazol-4-yl)piperazin-1-yl]methanone 6 (220mg, 841.64 umol, 31.76% yield, 95% purity) as a white semi solid. LC MS:ES+ 249.2. Note: In reaction diamide was formed, which was stirred withK2CO3 (1 eq.) for 30 mins to get desired product.

Step-4: Synthesis of1-(4-methoxybenzyl)-6-((4-(4-(1-methylcyclobutane-1-carbonyl)piperazin-1-yl)-1H-pyrazol-1-yl)methyl)benzo[cd]indol-2(1H)-one:To a stirred solution of6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 7(367.29 mg, 1.09 mmol) and(1-methylcyclobutyl)-[4-(1H-pyrazol-4-yl)piperazin-1-yl]methanone 6 (270mg, 1.09 mmol) in DMF (5 mL) was added Cesium carbonate (885.65 mg, 2.72mmol) at room temperature then reaction mixture was heated 80° C.overnight. Reaction mixture was diluted with cooled water extracted withethyl acetate. Combined organic layer was washed with saturated brinesolution and dried under reduced pressure to get crude which waspurified by combiflash chromatography using 30-40% EtOAc-Hexane aseluent to afford1-[(4-methoxyphenyl)methyl]-6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]pyrazol-1-yl]methyl]benzo[cd]indol-2-one8 (300 mg, 532.04 umol, 48.93% yield, 97.48% purity) as light yellowsolid. LC MS: ES+ 550.4.

Step-5: Synthesis of6-((4-(4-(1-methylcyclobutane-1-carbonyl)piperazin-1-yl)-1H-pyrazol-1-yl)methyl)benzo[cd]indol-2(1H)-one:To a stirred solution of1-[(4-methoxyphenyl)methyl]-6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]pyrazol-1-yl]methyl]benzo[cd]indol-2-one8 (150.00 mg, 272.90 umol) in TFA (3 mL) was addedtrifluoromethanesulfonic acid (327.65 mg, 2.18 mmol, 191.61 uL) at roomtemperature then reaction mixture was stirred at RT for over night.Reaction mixture was concentrated under reduced pressured to get crudemass which diluted with EtOAc and saturated solution of NaHCO₃, layerswere separated. Combined organic layer was washed with saturated brinesolution and dried under vacuum in rotavapor to afford6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one9 (115 mg, 238.29 umol, 87.32% yield, 89% purity) as brown gum. LC MS:ES+ 430.3.

Step-6: Synthesis of3-(6-((4-(4-(1-methylcyclobutane-1-carbonyl)piperazin-1-yl)-1H-pyrazol-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To the stirred solution of6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one9 (120.00 mg, 279.39 umol) in THF (5 mL) was added Sodium hydride (inoil dispersion) 60% dispersion in mineral oil (107.05 mg, 2.79 mmol, 60%purity) at cold condition and the reaction mixture was stirred at RT for10 minutes followed by portion wised addition of3-bromopiperidine-2,6-dione 10 (268.23 mg, 1.40 mmol) and the reactionwas heated at 70° C. for 1 hours. Reaction mixture was diluted withethyl acetate and washed with water; organic fraction separated. It wasdried over anhydrous sodium sulphate and evaporated under reducedpressure to obtain the crude which was purified by Prep TLC using 50%EtOAc-DCM as eluent to afford3-[6-[[4-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]pyrazol-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 246 (45 mg, 82.60 umol, 29.56% yield, 99.23% purity) as lightyellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.39 (d, J=8.28Hz, 1H), 8.10 (d, J=6.96 Hz, 1H), 7.85 (t, J=7.66 Hz, 1H), 7.44 (d,J=7.36 Hz, 1H), 7.39 (s, 1H), 7.20 (s, 1H), 7.12 (d, J=7.32 Hz, 1H),5.62 (s, 2H), 5.44 (dd, J=12.44, 4.92 Hz, 1H), 3.49-3.48 (m, 2H),3.33-3.31 (m, 2H), 2.95-2.93 (m, 1H), 2.77-2.76 (m, 5H), 2.66-2.62 (m,1H), 2.41-2.34 (m, 2H), 2.09-2.07 (m, 1H), 1.91-1.89 (m, 1H), 1.79-1.74(m, 2H), 1.61-1.58 (m, 1H), 1.32 (s, 3H) LC MS: ES+ 541.5.

Example 136. Synthesis of3-[6-[methoxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 247)

Step-1: Synthesis of6-[methoxy-[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate1a (400 mg, 891.84 umol) in Methanol (2 mL) was addeddiethyloxonio(trifluoro)boranuide (12.66 mg, 89.18 umol, 11.01 uL) andthe resultant reaction mixture was stirred at 100° C. for 1 hour. Aftercompletion of the reaction (monitored by TLC and LCMS) the reactionmixture was concentrated under reduced pressure and diluted with EtOAc.The organic part was then washed with water and brine, dried over sodiumsulphate and concentrated. The crude thus obtained was purified by PrepTLC plate (7% MeOH in DCM) to afford6-[methoxy-[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(1) (320 mg, 99% yield) as yellow solid. LC MS ES+ 363.2.

Step-2: Synthesis of6-[methoxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one:To the stirred solution of-[methoxy-[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(1) (325 mg, 896.74 umol) and 1-methylcyclobutanecarboxylic acid (2)(102.36 mg, 896.74 umol) in DMF (3 mL) was added DIPEA (579.49 mg, 4.48mmol, 780.98 uL) and stirred for 15 minutes followed by the addition ofHATU (511.45 mg, 1.35 mmol) and was allowed to stir for 16 hours at RT.After completion (monitored by LCMS), the reaction mixture was dilutedwith Ethyl acetate and washed with cold water, brine, dried over sodiumsulfate and concentrated under reduced pressure. The crude thus obtainedwas purified by column chromatography (silica, gradient: 0-2.5% MeOH inDCM) to afford6-[methoxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(3) (100 mg, 21.89% yield) as gummy solid. LC MS: ES+(M-31) 427.3

Step-3: Synthesis of3-[6-[methoxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[methoxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(3) (50 mg, 109.04 umol) in THF (3 mL) was added Sodium hydride 60%dispersion in mineral oil (41.78 mg, 1.09 mmol) at 0° C. and stirred for5 min. Then 3-bromopiperidine-2,6-dione (4) (104.68 mg, 545.20 umol) wasadded under cooling condition and the reaction mixture was stirred at70° C. for 60 min. After completion (monitored by TLC) the reactionmixture was quenched in ice and extracted with ethyl acetate. Theorganic part was further washed with water and brine, dried over sodiumsulfate and concentrated. The crude thus obtained was purified by PrepTLC Plate in 80% EtOAc in DCM to afford3-[6-[methoxy-[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 247 (20 mg, 30.59% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.39 (d, J=8.32 Hz, 1H), 8.08 (d, J=6.96 Hz,1H), 7.79 (t, J=7.64 Hz, 1H), 7.65 (s, 1H), 7.56 (d, J=7.12 Hz, 1H),7.32 (s, 1H), 7.14 (d, J=7.36 Hz, 1H), 5.84 (s, 1H), 5.45 (dd, J=12.8,5.2 Hz, 1H), 4.34-4.28 (m, 2H), 3.61-3.60 (m, 1H), 3.27 (s, 3H),3.05-2.91 (m, 2H), 2.78-2.63 (m, 3H), 2.41-2.32 (m, 2H), 2.11-2.08 (m,1H), 1.94-1.91 (m, 3H), 1.86-1.58 (m, 5H), 1.33 (s, 3H)LC MS: ES+(M-31)538.5.

Example 137. Synthesis of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate(Compound 248) and3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 249)

Step-1: Synthesis of tert-butyl4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate:In a sealed tube a stirred solution of tert-butyl4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (400 mg, 1.50 mmol) and6-bromo-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (553.02 mg, 1.50mmol) in tert butanol (2.50 mL), was added Cesium carbonate (734.00 mg,2.25 mmol) then reaction mixture was degassed for 5 min under argonatmosphere. Then added pd2(dba)3 (137.52 mg, 150.18 umol) and2-Dicyclohexylphosphino-2′,6′-di-I-propoxy-1,1′-biphenyl (70.08 mg,150.18 umol) then again purged for 2 min under argon atmosphere, thenthe reaction mixture was heated to 100° C. for 16 hr. After completionof the reaction mass added water then extracted with ethyl acetate thenorganic layers was washed with brine then dried with sodium sulphate andthen evaporated under reduced pressure to get the crude. This crude waspurified by combiflash column chromatography (using 50% ethyl acetate inhexane) to give the title compound tert-butyl4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate(500 mg, 812.79 umol, 54.12% yield, 90% purity) as orange solid. LCMS(ES+)=554.5 [M+H]+.

Step-2: Synthesis of6-[[1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one: To astirred solution of tert-butyl4-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate(300.00 mg, 541.86 umol) in Trifluroacetic acid (10 mL), reactionmixture was cooled to 0° C., was slowly added Trifluoromethanesulfonicacid (243.97 mg, 1.63 mmol, 142.67 uL) then reaction was stirred at 25°C. for 16 hr. After completion of SM, reaction mixture was concentratedunder reduced pressure, then dissolved in ice cold water and basified bysolid sodium bicarbonate and extracted with ethyl acetate, dried oversodium sulphate, concentrated under reduced pressure to give the titlecompound 6-[[1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one(150 mg, 382.44 umol, 70.58% yield, 85% purity) as orange solid. LCMS(ES+)=334.4 [M+H]+.

Step-3: Synthesis of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate:To a stirred solution of6-[[1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one (180 mg,539.91 umol) in DCM (10 mL), was added Triethylamine (163.90 mg, 1.62mmol, 225.76 uL) and followed by Di-tert-butyl dicarbonate (141.40 mg,647.90 umol, 148.69 uL), then the reaction mixture was stirred at 25° C.for 16 hr. After completion of the reaction, added water then extractedwith DCM then organic layers was washed with brine then dried withsodium sulphate and then evaporated under reduced pressure to get thecrude. This crude was purified by combiflash column chromatography(using ethyl acetate) to give the title compound tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate(200 mg, 424.45 umol, 78.61% yield, 92% purity) as orange solid. LCMS(ES+)=434.5 [M+H]+.

Step-4: Synthesis of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate:To a stirred solution of tert-butyl4-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate(150 mg, 346.02 umol) and 3-bromopiperidine-2,6-dione (664.39 mg, 3.46mmol) were in THF (10 mL), reaction mixture was cooled to 0° C., thenslowly drop wise added Sodium hydride (in oil dispersion) 60% dispersionin mineral oil (397.75 mg, 10.38 mmol, 60% purity). Reaction was slowlyrise the temperature up to RT and then stirred for 10 mins and thenheated to 65° C. for 16 hr. After that reaction was quenched by ice coldwater and extracted with ethyl acetate, separate the organic layer,dried over sodium sulphate, concentrated under reduced pressure to givethe crude. This crude was purified by prep-HPLC (100% acetonitrile) togive the title compound tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylateCompound 248 (30 mg, 53.89 umol, 15.57% yield, 97.82% purity) as orangesolid. LCMS (ES+)=543.2 [M−H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.07 (s,1H), 8.59-8.57 (d, 1H), 8.08-8.06 (t, 2H), 7.86 (s, 1H), 7.80-7.76 (t,1H), 7.49 (s, 1H), 6.90-6.88 (d, 1H), 6.66-6.64 (d, 1H), 5.39-5.37 (m,1H), 4.36-4.30 (m, 1H), 4.06-4.03 (m, 2H), 2.93-2.90 (m, 3H), 2.71-2.61(m, 2H), 2.07-2.00 (m, 3H), 1.85-1.75 (m, 2H), 1.41 (s, 9H).

Step-5: Synthesis of6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one:To a stirred solution of6-[[1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one (180 mg,539.91 umol) and 1-methylcyclobutanecarboxylic acid (73.95 mg, 647.90umol) in DMF (10 mL), was added DIPEA (209.34 mg, 1.62 mmol, 282.12 uL)and then followed by HATU (225.82 mg, 593.91 umol), then the reactionmixture was stirred at 25° C. for 16 hr. After completion of thereaction, added water then extracted with ethyl acetate then organiclayers was washed with brine then dried with sodium sulphate and thenevaporated under reduced pressure to get the crude. This crude waspurified by combiflash column chromatography (using ethyl acetate) togive the title compound6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one(105 mg, 220.02 umol, 40.75% yield, 90% purity) as orange solid. LCMS(ES+)=430.4 [M+H]+.

Step-6: Synthesis of3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one(65 mg, 151.33 umol) and 3-bromopiperidine-2,6-dione (116.23 mg, 605.34umol) were in THF (15 mL), reaction mixture was cooled to 0° C., thenslowly drop wise added Lithium bis(trimethylsilyl)amide (1 M, 1.21 mL).Reaction was slowly rise the temperature up to RT and then stirred for10 mins and then heated to 65° C. for 16 hr. After that reaction wasquenched by ice cold water and extracted with ethyl acetate, separatethe organic layer, dried over sodium sulphate, concentrated underreduced pressure to give the crude. This crude was purified by prep-TLC(using 80% ethyl acetate in DCM) to give the title compound3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 249 (10 mg, 18.19 umol, 12.02% yield, 98.36% purity) as orangesolid. LCMS (ES+)=541.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.08 (s,1H), 8.59-8.57 (d, 1H), 8.08-8.06 (t, 2H), 7.88 (s, 1H), 7.80-7.77 (t,1H), 7.48 (s, 1H), 6.91-6.89 (d, 1H), 6.67-6.65 (d, 1H), 5.40-5.35 (m,1H), 4.43-4.37 (m, 2H), 3.64 (m, 1H), 3.14 (m, 1H), 2.97-2.89 (m, 1H),2.74-2.65 (m, 2H), 2.45-2.42 (m, 3H), 2.07-2.04 (m, 3H), 1.96-1.92 (m,2H), 1.89-1.87 (m, 4H), 1.66 (m, 2H), 1.37-1.33 (s, 3H).

Example 138. Synthesis of tert-butyl4-[3-chloro-4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzoindol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate (Compound 250)and3-[6-[[3-chloro-1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 251)

Step-1: Synthesis of tert-butyl4-[3-chloro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate:In a sealed tube a stirred solution of tert-butyl4-(4-amino-3-chloro-pyrazol-1-yl)piperidine-1-carboxylate (1.3 g, 4.32mmol) and 6-bromo-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1.59g, 4.32 mmol) in tert butanol (25 mL), was added Cesium carbonate (2.11g, 6.48 mmol) then reaction mixture was degassed for 5 min under argonatmosphere. Then added pd2(dba)3 (395.77 mg, 432.20 umol) and2-Dicyclohexylphosphino-2′,6′-di-I-propoxy-1,1′-biphenyl (201.68 mg,432.20 umol) then again purged for 2 min under argon atmosphere, thenthe reaction mixture was heated to 100° C. for 16 hr. After completionof the reaction mass added water then extracted with ethyl acetate thenorganic layers was washed with brine then dried with sodium sulphate andthen evaporated under reduced pressure to get the crude. This crude waspurified by combiflash column chromatography (using 50% ethyl acetate inhexane) to give the title compound tert-butyl4-[3-chloro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate(2 g, 3.23 mmol, 74.75% yield, 95% purity) as orange solid. LCMS(ES+)=588.2 [M+H]+.

Step-2: Synthesis of6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo one: To astirred solution of tert-butyl4-[3-chloro-4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate(1 g, 1.70 mmol) in Trifluroacetic acid (10 mL), reaction mixture wascooled to 0° C., was slowly added Trifluoromethanesulfonic acid (765.59mg, 5.10 mmol, 447.71 uL) then reaction was stirred at 25° C. for 16 hr.After completion of SM, reaction mixture was concentrated under reducedpressure, then dissolved in ice cold water and basified by solid sodiumbicarbonate and extracted with ethyl acetate, dried over sodiumsulphate, concentrated under reduced pressure to give the title compound6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one(600 mg, 1.55 mmol, 91.13% yield, 95% purity) as orange solid; LCMS(ES+)=368.3 [M+H]+.

Step-3: Synthesis of tert-butyl4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate:To a stirred solution of6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one(150 mg, 407.80 umol) in DCM (10 mL), was added Triethylamine (123.79mg, 1.22 mmol, 170.52 uL) and followed by Di-tert-butyl dicarbonate(106.80 mg, 489.35 umol, 112.30 uL), then the reaction mixture wasstirred at 25° C. for 16 hr. After completion of the reaction, addedwater then extracted with DCM then organic layers was washed with brinethen dried with sodium sulphate and then evaporated under reducedpressure to get the crude. This crude was purified by combiflash columnchromatography (using ethyl acetate) to give the title compoundtert-butyl4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate(130 mg, 255.58 umol, 62.67% yield, 92% purity) as orange solid. LCMS(ES+)=468.1 [M+H]+.

Step-4: Synthesis of tert-butyl4-[3-chloro-4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylate:To a stirred solution of tert-butyl4-[3-chloro-4-[(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate(30 mg, 64.11 umol) in THF (5 mL), reaction mixture was cooled to 0° C.,then portion wise added Sodium hydride (in oil dispersion) 60%dispersion in mineral oil (24.56 mg, 641.10 umol, 60% purity). Reactionwas slowly rise the temperature up to RT and then stirred for 10 mins.After that 3-bromopiperidine-2,6-dione (61.55 mg, 320.55 umol) was addedslowly at RT, then again stirred for 10 mins and then heated to 65° C.for 1 hr. After completion of SM, reaction was quenched by ice coldwater and extracted with ethyl acetate, separate the organic layer,dried over sodium sulphate, concentrated under reduced pressure to givethe crude. This crude was purified by prep-TLC (using 70% ethyl acetatein DCM) to give the title compound tert-butyl4-[3-chloro-4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]amino]pyrazol-1-yl]piperidine-1-carboxylateCompound 250 (2 mg, 3.36 umol, 5.24% yield, 97.28% purity) as orangesolid. LCMS (ES+)=577.2 [M−H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.07 (s,1H), 8.60-8.57 (d, 1H), 8.09-8.08 (d, 1H), 8.03 (s, 1H), 7.85 (s, 1H),7.82-7.78 (t, 1H), 6.88-6.86 (d, 1H), 6.22-6.20 (d, 1H), 4.43-4.33 (m,1H), 4.03 (m, 2H), 2.92-2.89 (m, 2H), 2.70-2.60 (m, 2H), 2.05-2.02 (m,3H), 1.80-1.77 (m, 2H), 1.41 (m, 9H).

Step-5: Synthesis of6-[[3-chloro-1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one:To a stirred solution of6-[[3-chloro-1-(4-piperidyl)pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one(300 mg, 815.59 umol) and 1-methylcyclobutanecarboxylic acid (111.71 mg,978.71 umol) in DMF (15 mL), was added DIPEA (316.22 mg, 2.45 mmol,426.17 uL) and then followed by HATU (341.12 mg, 897.15 umol), then thereaction mixture was stirred at 25° C. for 16 hr. After completion ofthe reaction, added water then extracted with ethyl acetate then organiclayers was washed with brine then dried with sodium sulphate and thenevaporated under reduced pressure to get the crude. This crude waspurified by combiflash column chromatography (using ethyl acetate) togive the title compound6-[[3-chloro-1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one(120 mg, 237.95 umol, 29.18% yield, 92% purity) as orange solid. LCMS(ES+)=464.4 [M+H]+.

Step-6: Synthesis of3-[6-[[3-chloro-1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[3-chloro-1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-1H-benzo[cd]indol-2-one(64 mg, 137.94 umol) and 3-bromopiperidine-2,6-dione (79.46 mg, 413.83umol) were in THF (10 mL), reaction mixture was cooled to 0° C., thenslowly drop wise added Lithium bis(trimethylsilyl)amide (1 M, 689.72uL). Reaction was slowly rise the temperature up to RT and then stirredfor 10 mins and then heated to 65° C. for 16 hr. After that reaction wasquenched by ice cold water and extracted with ethyl acetate, separatethe organic layer, dried over sodium sulphate, concentrated underreduced pressure to give the crude. This crude was purified by prep-TLC(using 80% ethyl acetate in DCM) to give the title compound3-[6-[[3-chloro-1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]amino]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 251 (12 mg, 19.89 umol, 14.42% yield, 95.31% purity) as orangesolid. LCMS (ES+)=575.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.08 (s,1H), 8.60-8.58 (d, 1H), 8.10-8.08 (d, 1H), 8.05 (s, 1H), 7.86 (s, 1H),7.82-7.78 (t, 1H), 6.89-6.87 (d, 1H), 6.22-6.21 (d, 1H), 5.38-5.35 (m,1H), 4.41 (m, 3H), 3.63 (m, 1H), 3.13 (m, 1H), 2.93-2.89 (m, 2H),2.71-2.67 (m, 3H), 2.05-1.98 (m, 3H), 1.94-1.92 (m, 2H), 1.87-1.80 (m,4H), 1.63-1.61 (m, 1H), 1.37 (s, 3H).

Example 139. Synthesis of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-methyl-amino]pyrazol-1-yl]piperidine-1-carboxylate(Compound 252)

Step-1: Synthesis of tert-butyl4-[4-(benzyloxycarbonylamino)pyrazol-1-yl]piperidine-1-carboxylate: To astirred solution of tert-butyl4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate (1.5 g, 5.63 mmol) inDCM (20 mL), reaction was cooled to 0° C. then added Triethylamine (1.14g, 11.26 mmol, 1.57 mL) and the catalytic amount of DMAP (68.80 mg,563.19 umol) followed by drop wise added benzyl carbonochloridate(960.77 mg, 5.63 mmol, 800.64 uL). Then reaction mixture was stirred at25° C. for 2 hr. After completion of SM, reaction mixture was quenchedby saturated solution of sodium bicarbonate, extracted with DCM, driedover sodium sulphate, concentrated under reduced pressure to give thecrude. It was purified by combiflash column chromatography (eluted by40% ethyl acetate in n-hexane) to give the title compound tert-butyl4-[4-(benzyloxycarbonylamino)pyrazol-1-yl]piperidine-1-carboxylate (1.6g, 3.92 mmol, 69.52% yield, 98% purity) as brown sticky liquid. LCMS(ES+)=401.1 [M+H]+.

Step-2: Synthesis of tert-butyl4-[4-[benzyloxycarbonyl(methyl)amino]pyrazol-1-yl]piperidine-1-carboxylate:To a stirred solution of tert-butyl4-[4-(benzyloxycarbonylamino)pyrazol-1-yl]piperidine-1-carboxylate (1.7g, 4.25 mmol) in THF (35 mL), reaction was cooled to 0° C., then Sodiumhydride (in oil dispersion) 60% dispersion in mineral oil (2.55 mg, 6.37mmol, 60 purity) was added portion wise. Then reaction mixture wasstirred at 0° C. for 40 mins. After that Methyl iodide (D3) stored overCopper (1.21 g, 8.49 mmol, 528.53 uL) was added slowly drop wise intothe reaction mixture, then temp was rise up to RT, and reaction wasstirred at RT for 16 hr. After completion of SM, reaction mixture wasquenched by ice cold water, extracted with ethyl acetate, dried oversodium sulphate, concentrated under reduced pressure to give the crude.It was purified by combiflash column chromatography (eluted by 40% ethylacetate in n-hexane) to give the title compound tert-butyl4-[4-[benzyloxycarbonyl(methyl)amino]pyrazol-1-yl]piperidine-1-carboxylate(1.5 g, 3.51 mmol, 82.69% yield, 97% purity) as brown sticky liquid.LCMS (ES+)=415.1 [M+H]+.

Step-3: Synthesis of tert-butyl4-[4-(methylamino)pyrazol-1-yl]piperidine-1-carboxylate: To a stirredsolution of tert-butyl4-[4-[benzyloxycarbonyl(methyl)amino]pyrazol-1-yl]piperidine-1-carboxylate(1.6 g, 3.86 mmol) in Ethyl acetate (30 mL) and Methanol (6 mL), wasadded Palladium (1.64 g, 15.44 mmol) then reaction mixture was stirredat 25° C. for 16 hr under hydrogen atmosphere. After completion of SM,reaction mixture was filtered through celite bed and solution wasconcentrated under reduced pressure to give the title compoundtert-butyl 4-[4-(methylamino)pyrazol-1-yl]piperidine-1-carboxylate (1 g,3.39 mmol, 87.78% yield, 95% purity) as brown sticky liquid. LCMS(ES+)=281.4 [M+H]+.

Step-4: Synthesis of tert-butyl4-[4-[methyl-(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate:In a sealed tube the stirred solution of tert-butyl4-[4-(methylamino)pyrazol-1-yl]piperidine-1-carboxylate (500 mg, 1.78mmol) and 6-bromo-1H-benzo[cd]indol-2-one (442.41 mg, 1.78 mmol) in tertbutanol (15 mL), was added Cesium carbonate (871.60 mg, 2.68 mmol) thenreaction mixture was degassed for 5 min under argon atmosphere. Thenadded pd2(dba)3 (163.30 mg, 178.34 umol) and2-Dicyclohexylphosphino-2′,6′-di-I-propoxy-1,1′-biphenyl (166.25 mg,356.68 umol) then again purged for 2 min under argon atmosphere, thenthe reaction mixture was heated to 90° C. for 16 hr. After consumptionof SM reaction mixture was filtered through celite bed and concentratedin vacuo. Purification by combiflash column chromatography (eluted by40% ethyl acetate in n-hexane) to give the title compound tert-butyl4-[4-[methyl-(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate(280 mg, 563.09 umol, 31.57% yield, 90% purity) as yellow liquid. LCMS(ES+)=448.4 [M+H]+.

Step-5: Synthesis of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl-amino]pyrazol-1-yl]piperidine-1-carboxylate:To a stirred solution of tert-butyl4-[4-[methyl-(2-oxo-1H-benzo[cd]indol-6-yl)amino]pyrazol-1-yl]piperidine-1-carboxylate(80.00 mg, 178.76 umol) in DMF (5 mL), reaction mixture was cooled to 0°C., then added Sodium hydride (in oil dispersion) 60% dispersion inmineral oil (20.55 mg, 536.28 umol, 60% purity). Then reaction washeated to 60° C. for 30 min. After that 3-bromopiperidine-2,6-dione(68.65 mg, 357.52 umol) was added to that mixture, then continue heatingfor 4 to 6 hr. But SM was not fully consumed, then again added3-bromopiperidine-2,6-dione (68.65 mg, 357.52 umol) and reactioncontinue for 16 hr. After that reaction was diluted with water andextracted with ethyl acetate, dried over sodium sulphate, concentratedunder reduced pressure to give the crude. This crude was purified byprep-TLC (using ethyl acetate) to give the title compound tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-methyl-amino]pyrazol-1-yl]piperidine-1-carboxylateCompound 252 (9 mg, 15.35 umol, 8.59% yield, 95.28% purity) as orangesolid. LCMS (ES+)=559.6 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s,1H), 8.06-8.04 (d, 1H), 8.02-8.00 (d, 1H), 7.71 (t, 1H), 7.40 (s, 1H),7.16-7.14 (d, 1H), 7.07-7.05 (d, 2H), 5.42 (t, 1H), 4.22-4.19 (d, 1H),3.99-3.96 (m, 2H), 3.23 (s, 3H), 2.98-2.90 (m, 1H), 2.84-2.80 (m, 1H),2.76-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.44-2.41 (m, 1H), 2.10-2.09 (m,1H), 1.93-1.90 (m, 2H), 1.71-1.66 (m, 2H), 1.39 (s, 9H).

Example 140. Synthesis of3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrrolo[2,3-b]pyridin-3-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 253)

Step-1: Synthesis of tert-butyl4-(3-formylpyrrolo[2,3-b]pyridin-1-yl)piperidine-1-carboxylate: To astirred solution of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2 g, 13.68mmol) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (4.21g, 15.05 mmol) were in DMF (30 mL), was added Cesium carbonate (8.92 g,27.37 mmol) and the reaction mixture was heated at 90° C. for 16 hr.After completion of SM, reaction mixture was diluted with ethyl acetate,washed with water, separate the organic layer, dried over sodiumsulphate, concentrated under reduced pressure to give the crude. It waspurified by combiflash column chromatography (15% ethyl acetate inhexane) to give the title compound tert-butyl4-(3-formylpyrrolo[2,3-b]pyridin-1-yl)piperidine-1-carboxylate (2 g,5.89 mmol, 43.04% yield, 97% purity) as a white solid. LCMS (ES+)=330.2[M+H]+.

Step-2: Synthesis of tert-butyl4-[3-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrrolo[2,3-b]pyridin-1-yl]piperidine-1-carboxylate:To a stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (100.00 mg,403.10 umol) in THF (10 mL), reaction mixture was cooled to −78° C.,then Butyl Lithium (2.2 M, 732.92 uL) was added slowly drop wise andreaction was stirred at the same temperature for 40 mins. After thattert-butyl4-(3-formylpyrrolo[2,3-b]pyridin-1-yl)piperidine-1-carboxylate (132.78mg, 403.10 umol) in THF (10 mL) was added slowly dropwise into thereaction mixture, and reaction was stirred at the same temperature for40 min. After that reaction mixture was quenched by saturated solutionof ammonium chloride, extracted with ethyl acetate, dried over sodiumsulphate, concentrated under reduced pressure to give the crude. It waspurified by combiflash column chromatography (eluted by 70% ethylacetate in hexane) to give the title compound tert-butyl4-[3-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrrolo[2,3-b]pyridin-1-yl]piperidine-1-carboxylate(40 mg, 72.21 umol, 17.91% yield, 90% purity) as brown solid. LCMS(ES+)=281.4 [M+H]+.

Step-3: Synthesis of6-[[1-(4-piperidyl)pyrrolo[2,3-b]pyridin-3-yl]methyl]-1H-benzo[cd]indol-2-one:In a microwave a stirred solution of tert-butyl4-[3-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrrolo[2,3-b]pyridin-1-yl]piperidine-1-carboxylate(50 mg, 100.29 umol) in DCE (2 mL), was added Trifluoroacetic acid(91.48 mg, 802.29 umol, 61.81 uL) and Triethylsilane (46.65 mg, 401.15umol, 64.07 uL), then reaction mixture was heated to 70° C. for 0.5 hr.Crude LCMS showed the product mass. Reaction mixture was concentrated invacuo to give the title compound6-[[1-(4-piperidyl)pyrrolo[2,3-b]pyridin-3-yl]methyl]-1H-benzo[cd]indol-2-one(45 mg, 83.39 umol, 83.15% yield, 92% purity) as brown sticky liquid.LCMS (ES+)=383.3 [M+H]+.

Step-4: Synthesis of6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrrolo[2,3-b]pyridin-3-yl]methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of6-[[1-(4-piperidyl)pyrrolo[2,3-b]pyridin-3-yl]methyl]-1H-benzo[cd]indol-2-one(250 mg, 653.67 umol) and 1-methylcyclobutanecarboxylic acid (82.07 mg,719.04 umol) in THF (10 mL) was added DIPEA (253.45 mg, 1.96 mmol,341.57 uL) and 1-Propanephosphonic acid cyclic anhydride (311.98 mg,980.50 umol, 291.57 uL) reaction mixture was stirred at 25° C. for 16hr. According to LCMS there was shown the desired mass and the reactionmixture was diluted with ethyl acetate and washed with water, organiclayer separated, dried over sodium sulphate and concentrated underreduced pressure to give the crude. This crude was purified by columnchromatography (using 10% methanol in DCM) to give the title compound6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrrolo[2,3-b]pyridin-3-yl]methyl]-1H-benzo[cd]indol-2-one(120 mg, 225.67 umol, 34.52% yield, 90% purity) as brown solid. LCMS(ES+)=479.3 [M+H]+.

Step-6: Synthesis of3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrrolo[2,3-b]pyridin-3-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrrolo[2,3-b]pyridin-3-yl]methyl]-1H-benzo[cd]indol-2-one(40.00 mg, 83.58 umol) in DMF (5 mL), reaction mixture was cooled to 0°C., then added Sodium hydride (in oil dispersion) 60% dispersion inmineral oil (5.76 mg, 250.74 umol). Then reaction was heated to 60° C.for 30 min. After that 3-bromopiperidine-2,6-dione (32.10 mg, 167.16umol) was added to that mixture, then continue heating for 4 to 6 hr.But SM was not fully consumed, then again added3-bromopiperidine-2,6-dione (32.10 mg, 167.16 umol) and reactioncontinue for 16 hr. After that reaction was diluted with water andextracted with ethyl acetate, dried over sodium sulphate, concentratedunder reduced pressure to give the crude. This crude was purified byprep-TLC (using ethyl acetate) to give the title compound3-[6-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrrolo[2,3-b]pyridin-3-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 253 (6 mg, 9.30 umol, 11.13% yield, 91.39% purity) as lightyellow solid. LCMS (ES+)=590.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ11.10 (s, 1H), 8.50-8.48 (d, 1H), 8.19-8.18 (d, 1H), 8.07-8.06 (d, 1H),7.93-7.91 (d, 1H), 7.82 (t, 1H), 7.64 (s, 1H), 7.45-7.44 (d, 1H),7.06-7.00 (m, 2H), 5.44-5.41 (m, 1H), 4.89 (brs, 1H), 4.48 (s, 3H), 3.65(m, 1H), 3.17 (brs, 1H), 2.96-2.90 (m, 2H), 2.74-2.71 (m, 2H), 2.61 (m,1H), 2.08-2.07 (m, 1H), 1.92-1.80 (m, 7H), 1.65 (m, 1H).

Example 141. Synthesis of3-[6-[[4-[[4-(4-chloro-2-fluoro-phenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]-piperidine-2,6-dione(Compound 254) and3-[6-[[4-[[4-(4-chloro-2-fluoro-phenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 255)

Step-1: Synthesis of tert-butyl4-(4-chloro-2-fluorophenyl)piperazine-1-carboxylate: In a sealed tube astirred solution of 1-bromo-4-chloro-2-fluoro-benzene (300 mg, 1.43mmol, 178.57 uL) and tert-butyl piperazine-1-carboxylate (213.42 mg,1.15 mmol) intoluene (20 mL), was addedbenzyl-[1-[2-[benzyl(phenyl)phosphanyl]-1-naphthyl]-2-naphthyl]-phenyl-phosphane(18.64 mg, 28.65 umol) and sodium;2-methylpropan-2-olate (344.14 mg,3.58 mmol) then reaction mixture was degassed for 5 min under argonatmosphere. Then added Tris(dibenzylideneacetone)dipalladium(0) (26.23mg, 28.65 umol) then again purged for 2 min under argon atmosphere, thenthe reaction mixture was heated to 110° C. for 0.5 hr. After completionof the reaction, the mass was added to water and extracted with EtOAc.Combined organics was washed with water and brine and dried over sodiumsulphate. Crude was purified by combi-flash with eluting solventHex-EtOAc to get tert-butyl4-(4-chloro-2-fluoro-phenyl)piperazine-1-carboxylate (220 mg, 629.01umol, 43.91% yield, 90% purity) as yellow solid.

Step-2: Synthesis of 1-(4-chloro-2-fluorophenyl)piperazine: To an icecold solution of tert-butyl4-(4-chloro-2-fluorophenyl)piperazine-1-carboxylate (1.3 g, 4.36 mmol)in dioxane (20 mL) was added dioxane-HCl (4 M, 21.79 mL) and stirred at25° C. for 16 h. Crude LCMS showed complete consumption of SM andformation of product. The reaction mass was evaporated to dryness to getpure compound as HCl salt. LCMS (ES+)=215.2 [M+H]+.

Step-3: Synthesis of 1-(4-chloro-2-fluorophenyl)-4-(4-(chloromethyl)benzyl) piperazine: To a stirred solution of1-(4-chloro-2-fluoro-phenyl)piperazine; hydrochloride (2 g, 7.96 mmol)in DMF (15 mL) was added DIPEA (3.09 g, 23.89 mmol, 4.16 mL) and stirredfor 5 min. Then 1,4-bis(chloromethyl)-benzene (1.67 g, 9.56 mmol, 1.18mL) was added and the reaction was heated at 60° C. for 16 h. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wasdiluted with EtOAc and washed with water and brine, dried over sodiumsulfate and concentrated. The crude was purified by columnchromatography (100-200 silica, 25-30% EtOAc in hexane) to afford1-(4-chloro-2-fluoro-phenyl)-4-[[4-(chloromethyl)phenyl]methyl]piperazine(1.3 g, 3.31 mmol, 41.59% yield, 90% purity) as a white solid. LCMS(ES+)=354.4 [M+H]+.

Step-4: Synthesis of6-(4-((4-(4-chloro-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)benzo[cd]indol-2(1H)-one:To a stirred solution of1-(4-chloro-2-fluoro-phenyl)-4-[[4-(chloromethyl)phenyl]methyl]piperazine(700 mg, 1.98 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(643.31 mg, 2.18 mmol) in Ethanol (2 mL) and Toluene (4 mL) was addedPotassium phosphate tribasic anhydrous (1.26 g, 5.94 mmol) and thereaction mass was degassed under nitrogen atmosphere over 5 minutes.Then Tri-o-Tolyl phosphine (120.62 mg, 396.31 umol) and(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (181.45 mg, 198.15umol) were added to reaction mass, and degassed for another 5 min. Itwas then heated at 90° C. for 16 h. The reaction mixture was cooled toRT, diluted with EtOAc, filtered over celite, and concentrated underreduced pressure to get crude mass which was purified by Combi-flashColumn Chromatography using 20-80% EtOAc-Hex as eluent to afford6-[[4-[[4-(4-chloro-2-fluoro-phenyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one as yellowviscous liquid. LCMS (ES+)=486.3 [M+H]+.

Step-5: Synthesis of3-(6-(4-((4-(4-chloro-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To an ice cold solution of6-[[4-[[4-(4-chloro-2-fluoro-phenyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-ben-zo[cd]indol-2-one(280 mg, 576.16 umol) in THF (15 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (240.83 mg, 5.76 mmol, 55%purity) stirred at 25° C. for 10 mins. Compound3-bromopiperidine-2,6-dione (553.14 mg, 2.88 mmol) was added at a timeand again stirred for 10 mins at 25° C. The reaction was then heated to70° C. for 0.5 hr. Crude LCMS showed formation of product. The reactionwas cooled to RT and diluted with water and extracted with EtOAc. Thecombined organics was washed with water and brine and dried over sodiumsulphate. Crude was evaporated to dryness and purified by combiflashwith eluting solvent EtOAc in DCM to get3[6-[[4-[[4-(4-chloro-2-fluoro-phenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(190 mg, 295.94 umol, 51.36% yield, 93% purity) as yellow solid. LCMS(ES+)=597.6 [M+H]+.

Step-6: Chiral separation: Compound3-[6-[[4-[[4-(4-chloro-2-fluoro-phenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(166.59 mg, 279.01 umol) has been purified by following methodColumn:Column name:Chiralpak IC (21×250 mm), 5μ MobilePhase:DCM/Isopropanol:60/40, Flow rate:21.0 ml/min, Run time: 25 min.Wave length:254 nm Solubility:IPA & DCM to afford3-[6-[[4-[[4-(4-chloro-2-fluoro-phenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]-piperidine-2,6-dioneCompound 254 (50 mg, 80.12 umol, 28.71% yield, 95.67% purity) and3-[6-[[4-[[4-(4-chloro-2-fluoro-phenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 255 (52 mg, 81.23 umol, 29.11% yield, 93.27% purity) as yellowsolid. Compound 254: 1H NMR (400 MHz, MeOD): δ 8.25 (d, J=8 Hz, 1H),8.05 (d, J=8 Hz, 1H), 7.76 (t, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.26(q, J=8 Hz, 4H), 7.09-6.94 (m, 4H), 5.42-5.38 (m, 1H), 4.42 (s, 2H),3.53 (s, 2H), 3.038 (m, 4H), 2.96-2.92 (m, 1H), 2.84-2.80 (m, 2H), 2.59(m, 4H), 2.25-2.22 (m, 1H). LCMS (ES+)=597.2 [M+H]+. Compound 255: 1HNMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H) 8.34 (d, J=8 Hz, 1H), 8.08 (d,J=8 Hz, 1H), 7.82 (t, J=8 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.31-7.20 (m,4H), 7.16-7.09 (m, 2H), 7.01 (t, J=8 Hz, 1H), 5.46-5.41 (m, 1H), 4.38(s, 2H), 3.44 (s, 2H), 2.95 (m, 4H), 2.77-2.73 (m, 1H), 2.66-2.62 (m,2H), 2.10-2.07 (m, 2H). LCMS (ES+)=597.2 [M+H]+.

Example 142. Synthesis of3-(6-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 256) and3-(6-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 257)

Step-1: Synthesis of tert-butyl4-(2,4-difluorophenyl)piperazine-1-carboxylate: In a sealed tube astirred solution of 2,4-difluoro-1-iodo-benzene (2 g, 8.33 mmol, 995.02uL) and tert-butyl piperazine-1-carboxylate (2.33 g, 12.50 mmol) indioxane (20 mL), was added sodium;2-methyl-propan-2-olate (2.00 g, 20.83mmol) and dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (342.12mg, 833.37 umol) then reaction mixture was degassed for 5 min underargon atmosphere. Then added (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one;palladium (763.13 mg, 833.37 umol) then again purged for 2 min underargon atmosphere, then the reaction mixture was heated to 100° C. for 16hr. After completion of the reaction mass added to water then extractedwith EtOAc. Organic layer was washed with water, brine and dried oversodium sulphate. The evaporated crude was purified by combiflash columnchromatography (using 50% EtOAc in hexane) to get the title compoundtert-butyl 4-(2,4-difluoro-phenyl)piperazine-1-carboxylate (1.3 g, 3.09mmol, 37.13% yield, 71% purity) as off white solid. LCMS (ES+)=299.5[M+H]+.

Step-2: Synthesis of 1-(2,4-difluorophenyl)piperazine: To an ice coldsolution of tert-butyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate(1.3 g, 4.36 mmol) in dioxane (20 mL) was added dioxane-HCl (4 M, 21.79mL) and stirred at 25° C. for 16 h. Crude LCMS showed completeconsumption of SM and formation of product. The reaction mass wasevaporated to dryness to get pure compound as HCl salt. LCMS (ES+)=199.2[M+H]+.

Step-3: Synthesis of1-(4-(chloromethyl)benzyl)-4-(2,4-difluorophenyl)piperazine: To astirred solution of 1-(2,4-difluorophenyl)piperazine; hydrochloride (1g, 4.26 mmol) in DMF (30 mL) was added DIPEA (1.65 g, 12.78 mmol, 2.23mL) and stirred for 5 min. Then 1,4-bis(chloromethyl)-benzene (745.95mg, 4.26 mmol, 525.32 uL) was added and the reaction was heated at 60°C. for 16 h. After completion of the reaction (monitored by TLC), thereaction mixture was diluted with EtOAc and washed with water and brine,dried over sodium sulfate and concentrated. The crude was purified bycolumn chromatography (100-200 silica, 25-30% EtOAc in hexane) to afford1-[[4-(chloromethyl) phenyl]methyl]-4-(2,4-difluorophenyl)piperazine(400 mg, 1.16 mmol, 27.31% yield, 98% purity) as a white solid.

Step-4: Synthesis of6-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)benzo[cd]indol-2(1H)-one:To a stirred solution of1-[[4-(chloromethyl)phenyl]methyl]-4-(2,4-difluorophenyl)piperazine (400mg, 1.19 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(701.03 mg, 2.38 mmol) in Ethanol (2 mL) and Toluene (4 mL) was addedPotassium phosphate tribasic anhydrous (756.29 mg, 3.56 mmol) andTri-o-Tolyl phosphine (72.30 mg, 237.53 umol) and the reaction wasdegassed under argon atmosphere over 5 minutes. Then(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (108.75 mg, 118.76umol) was added to this reaction mass, and degassed for another 5 min.It was then heated at 100° C. for 16 hr. Product was formed according toLCMS. The reaction mixture was cooled to RT, diluted with EtOAc andwater, filtered over celite, organics was separated, washed with waterfollowed by brine and dried over sodium sulphate and concentrated underreduced pressure to get crude mass, which was purified by Combi-flashColumn Chromatography using 20-80% EtOAc-Hex as eluent to afford6-[[4-[[4-(2,4-difluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(250 mg, 431.29 umol, 36.32% yield, 81% purity) as off white solid. LCMS(ES+)=470.3 [M+H]+.

Step-5: Synthesis of3-(6-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1-(2H)yl)piperidine-2,6-dione:To an ice cold solution of6-[[4-[[4-(2,4-difluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-1H-benzo[cd]-indol-2-one(250 mg, 532.45 umol) in THF (5 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (127.78 mg, 5.32 mmol) stirredat 25° C. for 10 mins. Compound 3-bromopiperidine-2,6-dione (511.18 mg,2.66 mmol) was added at a time and again stirred for 10 mins at 25° C.The reaction was then heated to 70° C. for 0.5 hr. Crude LCMS showedformation of product. The reaction was cooled to RT and diluted withwater and extracted with EtOAc. The combined organics was washed withwater and brine and dried over sodium sulphate. Crude was evaporated todryness and purified by combi-flash with eluting solvent EtOAc in DCM toget3-[6-[[4-[[4-(2,4-difluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(190 mg, 317.42 umol, 59.61% yield, 97% purity) as yellow solid. LCMS(ES+)=581.6 [M+H]+.

Step-6: Chiral separation: Compound3-[6-[[4-[[4-(2,4-difluorophenyl)piperazin-1-yl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(162 mg, 279.01 umol) has been purified by following method Column:Chiralpak IC (20×250 mm), 5μ Mobile Phase: DCM/IPA:50/50, No Modifieradded Flow rate: 18 ml/min, Run time: 18 min. Wave length: 224 nmSolubility: DCM only. Isomer I Compound 256: 1H NMR (400 MHz, DMSO-d6):δ 11.12 (s, 1H) 8.34 (d, J=8 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.83 (t, J=8Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.26-7.18 (m, 4H), 7.05-6.98 (m, 2H),7.05-7.01 (m, 2H), 5.46-5.42 (m, 1H), 4.38 (s, 2H), 3.44 (s, 2H), 2.91(m, 5H), 2.80-2.62 (m, 2H), 2.50-2.46 (m, 4H), 2.10-2.07 (m, 2H). LCMS(ES+)=581.2 [M+H]+. Isomer II Compound 257: 1H NMR (400 MHz, DMSO-d6): δ11.12 (s, 1H) 8.34 (d, J=8 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.82 (t, J=8Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.26-7.09 (m, 5H), 7.05-6.98 (m, 2H),5.46-5.42 (m, 1H), 4.38 (s, 2H), 3.44 (s, 2H), 2.98-2.91 (m, 4H),2.79-2.62 (m, 2H), 2.49 (m, 4H), 2.10-2.07 (m, 2H). LCMS (ES+)=581.2[M+H]+.

Example 143. Synthesis of3-(6-(4-((4-(4-fluorophenoxy)piperidin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 258)

Step-1: Synthesis of3-(6-(4-((4-(4-fluorophenoxy)piperidin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To the stirred solution of4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]benzaldehyde(250 mg, 627.49 umol) in THF (6 mL) was added4-(4-fluorophenoxy)piperidine (122.51 mg, 627.49 umol) followed by theaddition of dibutyltin(2+);dichloride (228.79 mg, 752.99 umol, 168.23uL) and phenylsilane (67.90 mg, 627.49 umol, 77.43 uL). The reactionmixture was then stirred at 90° C. for 16 hours in a sealed tube. TLCshowed formation of new spot. The reaction mixture was diluted withethyl acetate, washed with water and brine solution. The organicfraction was separated. It was dried over anhydrous sodium sulphate,evaporated under reduced pressure to obtain the crude compound which waspurified by flash chromatography using 0-5% MeOH-DCM to afford3-[6-[[4-[[4-(4-fluorophenoxy)-1-piperidyl]methyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 258 (22 mg, 37.78 umol, 6.02% yield, 99.2% purity) as yellowsolid. 1H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.31 (d, J=8 Hz, 1H),8.05 (d, J=8 Hz, 1H), 7.80 (t, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 1H),7.21-7.15 (m, 4H), 7.08-7.02 (m, 3H), 6.90 (bs, 2H) 5.42-5.39 (m, 1H),4.34 (s, 2H), 4.24 (s, 1H), 3.37 (s, 2H) 2.95-2.88 (m, 1H), 2.77-2.70(m, 1H), 2.67-2.59 (m, 3H), 2.12-2.06 (m, 3H), 2.04 (m, 2H), 1.54 (m,2H), LCMS (ES+)=578.2 [M+H]+.

Example 144. Synthesis of3-(6-((1-((1r,4r)-4-neopentylcyclohexyl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 259) and3-(6-((1-((1s,4s)-4-neopentylcyclohexyl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 260)

Step-1: Synthesis of 4-neopentylcyclohexan-1-ol: To a solution of4-(2,2-dimethylpropyl)phenol (1 g, 6.09 mmol) in hexane (30 mL) wasadded trichlororhodium; hydrate (138.38 mg, 608.85 umol),Tetrabutylammonium hydrogen sulfate (206.73 mg, 608.85 umol) and buffer(6.09 mmol. 30 mL) (phosphate buffer of pH 7.4) reaction was stirredunder hydrogen pressure 100 psi in a perr autoclave at 25° C. for 48 hr.Product was formed according to GCMS. The reaction was diluted withwater and EtOAc. Organics was separated, and washed with water and brineand dried over sodium sulphate. Evaporated organics was purified bycombiflash using 10-50% EtOAc in hexane to afford4-(2,2-dimethylpropyl)cyclohexanol (380 mg, 2.01 mmol, 32.99% yield, 90%purity) as low melting solid. Phosphate Buffer: 800 mL of distilledwater was taken in a suitable container. 20.214 g of Na₂HPO₄-7H₂O and3.394 g of NaH2PO4H2O was added to the solution. Adjusted solution tofinal desired pH using HCl or NaOH. Distilled water was added untilvolume is 1 L.

Step-2: Synthesis of 4-neopentylcyclohexyl methanesulfonate: To an icecold solution of 4-(2,2-dimethylpropyl)cyclohexanol (120 mg, 704.68umol) in DCM (10 mL) was added triethylamine (142.61 mg, 1.41 mmol,196.44 uL) followed by mesyl chloride (88.79 mg, 775.14 umol, 60.00 uL).The reaction was allowed to RT for 2 h. TLC showed formation of newspot. The reaction was diluted with water and DCM. The organics wasseparated. Combined organics was washed with water, brine and dried oversodium sulphate. The organics was evaporated to dryness to get[4-(2,2-dimethylpropyl)cyclohexyl]methanesulfonate (170 mg, 342.22 umol,48.56% yield, 50% purity) as crude.

Step-3: Synthesis of1-(4-methoxybenzyl)-6-((1-(4-neopentylcyclohexyl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one:To the solution of1-[(4-methoxyphenyl)methyl]-6-(1H-pyrazol-4-ylmethyl)benzo[cd]indol-2-one(3.47 g, 9.39 mmol) and[4-(2,2-dimethylpropyl)cyclohexyl]methanesulfonate (3.50 g, 14.09 mmol)in DMF (45 mL) in a sealed tube was added Cesium carbonate (6.12 g,18.79 mmol) and heated to 90° C. for 16 hr. Crude LCMS showed formationof product. The reaction was cooled to RT and diluted with water, EtOAc.Organics was separated. Combined organics was washed with water, brineand dried over sodium sulphate. Crude organics was evaporated to drynessand purified by combiflash using EtOAc in hexane to afford6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo-[cd]indol-2-one(2.1 g, 3.62 mmol, 38.57% yield, 90% purity) as yellow sticky gel. LCMS(ES+)=522.5 [M+H]+.

Step-4: Synthesis of6-((1-(4-neopentylcyclohexyl)-1H-pyrazol-4-yl)methyl)benzo 2(1H)-one: Tothe stirred solution of6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (200 mg, 383.37 umol) in TFA (3 mL) wasadded triethylsilane (178.31 mg, 1.53 mmol, 244.93 uL) and the reactionmixture was heated at 90° C. for 2 hr in a sealed tube. TLC showedcomplete consumption of the starting material along with the formationof the desired spot. The solvent in the reaction mixture was evaporatedunder reduced pressure and triturated with ether to obtain6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(18 mg, 42.59 umol, 11.11% yield, 95% purity) as crude.

Step-5: Separation of cis/trans isomers: Crude was separated ascis/trans by SFC, using Column: Regis Reflect C-Amylose A (250×30 mm)5μ. Flow: 25g/min Mobile Phase:50% CO₂+50% (0.3% Isopropylamine in MeOH)ABPR:100 bar Temperature:35° C. Isomer I 6a(6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(18 mg, 42.59 umol, 11.11% yield, 95% purity): 18 mg. Isomer 6b(6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(40 mg, 94.64 umol, 24.69% yield, 95% purity): 40 mg.

Step-6a: Synthesis of3-(6-((1-((1r,4r)-4-neopentylcyclohexyl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To an ice cold solution of6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(250 mg, 622.60 umol) (Isomer II) in THF (20 mL) was added Sodiumhydride (in oil dispersion) 60% dispersion in mineral oil (271.65 mg,6.23 mmol, 55% purity) stirred at 25° C. for 10 mins. Compound3-bromopiperidine-2,6-dione (119.55 mg, 622.60 umol) was added at a timeand again stirred for 10 mins at 25° C. The reaction was then heated to70° C. for 0.5 hr. Crude LCMS showed formation of product. The reactionwas cooled to RT and diluted with water and extracted with EtOAc. Thecombined organics was washed with water and brine and dried over sodiumsulphate. Crude was evaporated to dryness and purified by combiflashwith eluting solvent EtOAc in DCM to get3-[6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 259 (235 mg, 448.14 umol, 71.98% yield, 97.76% purity) asyellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (bs, 1H), 8.37 (d, J=8Hz, 1H), 8.09 (d, J=8 Hz, 1H), 7.84 (t, J=8 Hz, 1H), 7.51 (s, 1H), 7.35(d, J=8 Hz, 1H), 7.27 (s, 1H), 7.07 (d, J=8 Hz, 1H), 5.45-5.41 (m, 1H),4.17 (s, 2H), 3.99-3.93 (m, 1H), 2.94-2.90 (m, 1H), 2.75-2.72 (m, 1H),2.66-2.62 (m, 1H), 2.09-2.06 (m, 1H), 1.90-1.87 (m, 2H), 1.77-1.62 (m,4H), 1.35 (bs, 2H), 1.23 (bs, 2H), 1.17-1.03 (m, 4H), 0.87 (s, 9H). LCMS(ES+)=513.3 [M+H]+.

Step-6b: Synthesis of3-(6-((1-((1s,4s)-4-neopentylcyclohexyl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To an ice cold solution of6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(68.00 mg, 169.35 umol) (Isomer I) in THF (20 mL) was added Sodiumhydride (in oil dispersion) 60% dispersion in mineral oil (73.89 mg,1.69 mmol, 55% purity) stirred at 25° C. for 10 mins. Compound3-bromopiperidine-2,6-dione (162.58 mg, 846.73 umol) was added at a timeand again stirred for 10 mins at 25° C. The reaction was then heated to70° C. for 0.5 hr. Crude LCMS showed formation of product. The reactionwas cooled to RT and diluted with water and extracted with EtOAc. Thecombined organics was washed with water and brine and dried over sodiumsulphate. Crude was evaporated to dryness and purified by combiflashwith eluting solvent EtOAc in DCM to get3-[6-[[1-[4-(2,2-dimethylpropyl)cyclohexyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 260 (51 mg, 97.34 umol, 57.48% yield, 97.84% purity) as yellowsolid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (bs, 1H), 8.38 (d, J=8 Hz,1H), 8.09 (d, J=8 Hz, 1H), 7.84 (t, J=8 Hz, 1H), 7.58 (s, 1H), 7.36 (d,J=8 Hz, 1H), 7.28 (s, 1H), 7.08 (d, J=8 Hz, 1H), 5.44-5.42 (m, 1H), 4.18(s, 2H), 4.038 (m, 1H), 2.94-2.91 (m, 1H), 2.76-2.72 (m, 1H), 2.66-2.62(m, 1H), 2.07 (m, 1H), 1.92-1.89 (m, 2H), 1.72-1.65 (m, 3H), 1.56-1.50(bs, 2H), 1.40 (bs, 2H), 1.17-1.15 (m, 2H), 0.86 (s, 9H). LCMS(ES+)=513.3 [M+H]+.

Example 145. Synthesis ofN-cyclopropyl-4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-N-methylpiperidine-1-carboxamide(Compound 261)

Step-1: Synthesis of 4-nitrophenyl cyclopropyl(methyl)carbamate: To asolution of (4-nitrophenyl) carbonochloridate (500 mg, 2.48 mmol) in DCM(10 mL) was added Triethylamine (753.04 mg, 7.44 mmol, 1.04 mL) andfollowed by N-methylcyclopropanamine (176.42 mg, 2.48 mmol, 297.41 uL).The reaction was stirred at rt for 3 h. Crude TLC showed completeconsumption of SM and formation of new polar spot. The reaction wasadded to water and extracted with DCM. The combined organics was washedwith water and brine and dried over sodium sulphate. Crude wasevaporated to dryness to get(4-nitrophenyl)N-cyclopropyl-N-methyl-carbamate (360 mg, 761.99 umol,30.72% yield, 50% purity) as off-white solid. LCMS (ES+)=237.2 [M+H]+.

Step-2: Synthesis ofN-cyclopropyl-4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-N-methylpiperidine-1-carboxamide:To a solution of3-[2-oo-6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione(137.41 mg, 309.83 umol, 021) and(4-nitrophenyl)N-cyclopropyl-N-methyl-carbamate (109.78 mg, 464.74 umol)in DMF (6 mL) was added triethyl amine (94.05 mg, 929.48 umol, 129.55uL) and continued at 100° C. for 16 hr. Crude LCMS showed formation ofproduct with some SM-2. The reaction was cooled to RT and diluted water.The whole mass was extracted with EtOAc. Combined organics was washedwith water, brine and dried over sodium sulphate. Evaporated mass waspurified by prep TLC with eluting solvent acetone DCM to affordN-cyclopropyl-4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo-[cd]indol-6-yl]methyl]pyrazol-1-yl]-N-methyl-piperidine-1-carboxamideCompound 261 (40 mg, 71.48 umol, 23.07% yield, 96.61% purity) as yellowsolid. 1H NMIR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.38 (d, J=8 Hz, 1H)8.09 (d, J=8 Hz, 1H), 7.85 (t, J=8 Hz, 1H), 7.58 (s, 1H), 7.36 (d, J=8Hz, 1H), 7.31 (s, 1H), 7.08 (d, J=8 Hz, 1H), 5.45-5.42 (m, 1H),4.21-4.18 (m, 3H), 3.76-3.72 (m, 2H), 2.94 (m, 1H), 2.82-2.73 (m, 2H),2.71 (s, 3H), 2.66-2.62 (m, 1H), 2.57 (m, 1H), 2.09-2.08 (m, 1H),1.90-1.87 (m, 2H), 1.79-1.74 (m, 2H), 1.23 (s, 1H), 0.63-0.62 (m, 2H),0.47 (bs, 2H). LCMS (ES+)=541.2 [M+H]+.

Example 146. Synthesis of4-[4-(1-{4-[1-(2,6-Dioxo-piperidin-3-yl)-2-oxo-1,2-dihydro-benzo[cd]indol-6-ylmethyl]-phenyl}-cyclopropyl)-piperazin-1-yl]-3-fluoro-benzonitrile(Compound 262)

Step-1: Synthesis of 1-(4-Bromo-phenyl)-cyclopropylamine: To a stirredsolution of tert-butyl N-[1-(4-bromophenyl)cyclopropyl]carbamate (3.0 g,9.61 mmol) in 1,4-Dioxane (30 mL) was added Hydrogen chloride solution4.0M in dioxane (4.0 M, 24.02 mL) at RT and reaction mixture was stirredat RT for 16 hr. The progress of the reaction was monitored by TLC,after reaction completion reaction mixture was concentrated underreduced pressure the resultant compound was triturated with ether to get1-(4-bromophenyl)cyclopropanamine (2.2 g, 8.41 mmol, 87.51% yield, 95%purity) as off-white solid. LC-MS: (ES+)=212.0, 214.0 [M+H]+.

Step-2: Synthesis of1-[1-(4-Bromo-phenyl)-cyclopropyl]-4-(toluene-4-sulfonyl)-piperazine:Taken 1-(4-bromophenyl)cyclopropanamine (3.0 g, 12.07 mmol, 021) andN,N-bis(2-chloroethyl)-4-methyl-benzenesulfonamide (3.58 g, 12.07 mmol)in sealed tube and DIPEA (23.40 g, 181.05 mmol, 31.54 mL) was added andreaction mixture was stirred at 120° C. for 24 hr. The progress of thereaction was monitored by TLC, after reaction completion reactionmixture was diluted with ethyl acetate and gave water wash and brinewash separate out organic layer dried over anhydrous sodium sulfatefiltered and concentrated under reduced pressure to get the crudecompound and it was purified by column chromatography eluted with 0 to20% ethyl acetate in Hexane to get1-[1-(4-bromophenyl)cyclopropyl]-4-(p-tolylsulfonyl)piperazine (1.5 g,3.27 mmol, 27.12% yield, 95% purity) as off-white solid. LC-MS:(ES+)=434.8, 436.8 [M+H]+.

Step-3: Synthesis of 1-[1-(4-Bromo-phenyl)-cyclopropyl]-piperazine:Hydrobromic acid, 48% (29.80 g, 368.30 mmol, 20 mL) was added to1-[1-(4-bromophenyl)cyclopropyl]-4-(p-tolylsulfonyl)piperazine (1.0 g,2.30 mmol) at RT and reaction mixture was stirred at RT for 24 hr. Theprogress of the reaction was monitored by TLC, after reaction completionreaction mixture was concentrated under reduced pressure and resultantcompound was dissolved in water and adjusted pH with sodium bi carbonateand extracted with ethyl acetate and organic layer was washed with brinesolution separate out organic layer dried over anhydrous sodium sulfatefiltered and concentrated under reduced pressure to get1-[1-(4-bromophenyl)cyclopropyl]piperazine (0.600 g, 2.09 mmol, 91.04%yield, 98% purity) as off-white solid. LC-MS: (ES+)=283.2 [M+H]+.

Step-4: Synthesis of4-[1-(4-Bromo-phenyl)-cyclopropyl]-piperazine-1-carboxylic acidtert-butyl ester: To a stirred solution of1-[1-(4-bromophenyl)cyclopropyl]piperazine (0.600 g, 2.13 mmol) in THF(10 mL) was added Triethyl amine (323.88 mg, 3.20 mmol, 446.11 uL) andfollowed by Di-tert-butyl dicarbonate (931.38 mg, 4.27 mmol, 979.37 uL)was added and reaction mixture was stirred at RT for 2 hr. The progressof the reaction was monitored by TLC, after reaction completion reactionmixture was concentrated and direct purified by column chromatographyeluted with 0 to 20% ethyl acetate in Hexane to get tert-butyl4-[1-(4-bromophenyl)cyclopropyl]piperazine-1-carboxylate (0.500 g, 1.25mmol, 58.38% yield, 95% purity) as off-white solid. LC-MS: (ES+)=381.0[M+H]+.

Step-5: Synthesis of4-{1-[4-(4,4,5,5-Tetramethyl-11,3,21dioxaborolan-2-yl)-phenyl]-cyclopropyl}-piperazine-1-carboxylicacid tert-butyl ester: To a stirred solution of tert-butyl4-[1-(4-bromophenyl)cyclopropyl]piperazine-1-carboxylate (2.0 g, 5.25mmol) in 1,4-Dioxane (20 mL) in a sealed tube was added4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.33 g, 5.25 mmol) then Potassium Acetate (1.29 g, 13.11 mmol, 819.70uL) was added and degassed for 10 mins, later[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (214.17 mg, 262.26 umol) was added and againdegassed for 10 mins, after degassing reaction mixture was closed withteflon cap and stirred at 90° C. for 16 hr. The progress of the reactionwas monitored by TLC, after reaction completion reaction mixture wasfiltered and concentrated and crude was purified by columnchromatography eluted with 0 to 15% ethyl acetate in Hexane to gettert-butyl4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]piperazine-1-carboxylate(2.0 g, 4.44 mmol, 84.56% yield, 95% purity) as off-white solid. LC-MS:(ES+)=429.0 [M+H]+.

Step-6: Synthesis of4-(1-{4-[1-(4-Methoxy-benzyl)-2-oxo-1,2-dihydro-benzo[cd]indol-6-ylmethyl]-phenyl}-cyclopropyl)-piperazine-1-carboxylicacid tert-butyl ester: To a stirred solution of6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (2.0 g,5.92 mmol) and tert-butyl4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]piperazine-1-carboxylate(2.54 g, 5.92 mmol) in a mixture of Toluene (12 mL) and Ethanol (6 mL)was added Tripotassium phosphate (3.14 g, 14.80 mmol) then degassed for10 mins, later Tris(o-tolyl)phosphine (360.41 mg, 1.18 mmol) andTris(dibenzylideneacetone)dipalladium(0) (542.17 mg, 592.07 umol) wasadded and again degassed for 10 mins, after degassing reaction mixturewas closed with teflon cap and stirred at 90° C. for 16 hr. The progressof the reaction was monitored by TLC, after reaction completion reactionmixture was diluted with ethyl acetate gave water wash and brine wash,separate out organic layer dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to get the crude compound and itwas purified by column chromatography eluted with 10 to 50% ethylacetate in Hexane to get tert-butyl4-[1-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]cyclopropyl]piperazine-1-carboxylate(0.900 g, 1.46 mmol, 24.67% yield, 98% purity) as off-white solid.LC-MS: (ES+)=604.5 [M+H]+.

Step-7: Synthesis of6-[4-(1-Piperazin-1-yl-cyclopropyl)-benzyl]-1H-benzo[cd]indol-2-one: Toa stirred solution of tert-butyl4-[1-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]cyclopropyl]piperazine-1-carboxylate(0.400 g, 662.53 umol) in Trifluoro acetic acid (5 mL) was added Triflicacid (994.30 mg, 6.63 mmol, 581.46 uL) at RT 0° C. then reaction mixturewas stirred at RT for 16 hr. The progress of the reaction was monitoredby TLC, after reaction completion reaction mixture was concentratedunder reduced pressure then crude was dissolved in water and pH wasadjusted with sodium bi carbonate with 8 and extracted with ethylacetate gave brine wash separate out organic layer dried over anhydroussodium sulfate filtered and concentrated under reduced pressure to getthe compound as yellow solid. LC-MS: (ES+)=384.3 [M+H]+.

Step-8: Synthesis of3-Fluoro-4-(4-{1-[4-(2-oxo-1,2-dihydro-benzo[cd]indol-6-ylmethyl)-phenyl]-cyclopropyl}-piperazin-1-yl)-benzonitrile:To a stirred solution of6-[[4-(1-piperazin-1-ylcyclopropyl)phenyl]methyl]-1H-benzo[cd]indol-2-one(0.250 g, 651.92 umol) in NMP (2 mL) was added 3,4-difluorobenzonitrile(181.37 mg, 1.30 mmol) then DIPEA (210.64 mg, 1.63 mmol, 283.88 uL) wasadded in a sealed tube then closed with teflon cap and stirred at 100°C. for 16 hr. The progress of the reaction was monitored by TLC, afterreaction completion reaction mixture was quenched with chilled water andextracted with ethyl acetate and gave brine wash, separate out organiclayer dried over anhydrous sodium sulfate filtered and concentratedunder reduced pressure to get the crude compound and it was purified bycolumn chromatography eluted with 1 to 5% MeOH in DCM to get3-fluoro-4-[4-[1-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]cyclopropyl]piperazin-1-yl]benzonitrile(0.150 g, 283.54 umol, 43.49% yield, 95% purity) as yellow solid. LC-MS:(ES+)=503.4 [M+H]+.

Step-9: Synthesis of4-[4-(1-{4-[1-(2,6-Dioxo-piperidin-3-yl)-2-oxo-1,2-dihydro-benzo[cd]indol-6-ylmethyl]-phenyl}-cyclopropyl)-piperazin-1-yl]-3-fluoro-benzonitrile:To a stirred solution of3-fluoro-4-[4-[1-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]phenyl]cyclopropyl]piperazin-1-yl]benzonitrile(0.150 g, 298.46 umol) in THF (5 mL) was cooled to 0° C. then Sodiumhydride (in oil dispersion) 60% dispersion in mineral oil (143.25 mg,3.58 mmol, 60% purity) was added portion wise, later reaction mixturewas stirred at 0° C. for 15 mins, later 3-bromopiperidine-2,6-dione(343.84 mg, 1.79 mmol) was added and reaction mixture was stirred at RTfor 30 mins, later it was stirred at 70° C. for 16 hr. The progress ofthe reaction was monitored by TLC after reaction completion reactionmixture was quenched with chilled water and extracted with ethyl acetategave brine wash to the organic layer, separate out organic layer, driedover anhydrous sodium sulfate filtered and concentrated under reducedpressure to get the crude compound and it was purified by prep. HPLC toget4-[4-[1-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]cyclopropyl]piperazin-1-yl]-3-fluoro-benzonitrileCompound 262 (10 mg, 16.09 umol, 5.39% yield, 98.76% purity) as yellowsolid. 1HNMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.35-8.33 (d, J=8 Hz,1H), 8.07-8.05 (d, J=8 Hz, 1H), 7.82-7.78 (m, 1H), 7.64-7.60 (m, 1H),7.51-7.49 (m, 1H), 7.41-7.39 (m, 1H), 7.26-7.24 (m, 2H), 7.19-7.17 (m,2H), 7.11-7.09 (m, 1H), 7.04-7.00 (m, 1H), 5.44-5.42 (m, 1H), 4.38 (s,2H), 3.16 (m, 4H), 2.97-2.91 (m, 2H), 2.79-2.72 (m, 2H), 2.66-2.62 (m,2H), 2.08-2.07 (m, 2H), 0.85 (m, 2H), 0.71 (m, 2H), LC-MS: (ES+)=614.3[M+H]+.

Example 147. Synthesis of3-[6-(4-{1-[4-(1-Methyl-cyclobutanecarbonyl)-piperazin-1-yl]-cyclopropyl}-benzyl)-2-oxo-2H-benzo[cd]indol-1-yl]-piperidine-2,6-dione(Compound 263)

Step-1: Synthesis of6-[4-(1-Piperazin-1-yl-cyclopropyl)-benzyl]-1H-benzo[cd]indol-2-one: Toa stirred solution of tert-butyl4-[1-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]cyclopropyl]piperazine-1-carboxylate(0.400 g, 662.53 umol) in Trifluoro acetic acid (5 mL) was added Triflicacid (994.30 mg, 6.63 mmol, 581.46 uL) at RT 0° C. then reaction mixturewas stirred at RT for 16 hr. The progress of the reaction was monitoredby TLC, after reaction completion reaction mixture was concentratedunder reduced pressure then crude was dissolved in water and pH wasadjusted with sodium bi carbonate with 8 and extracted with ethylacetate gave brine wash separate out organic layer dried over anhydroussodium sulfate filtered and concentrated under reduced pressure to getthe compound as yellow solid. LC-MS: (ES+)=384.3 [M+H]+.

Step-2: Synthesis of6-(4-{1-[4-(1-Methyl-cyclobutanecarbonyl)-piperazin-1-yl]-cyclopropyl}-benzyl)-1H-benzo[cd]indol-2-one:To a stirred solution of6-[[4-(1-piperazin-1-ylcyclopropyl)phenyl]methyl]-1H-benzo[cd]indol-2-one(0.100 g, 260.77 umol) in DMF (2 mL) was added1-methylcyclobutanecarboxylic acid (59.53 mg, 521.53 umol) thenN,N-Diisopropylethylamine (101.11 mg, 782.30 umol, 136.26 uL) was addedand finally HATU (247.88 mg, 651.92 umol) was added and reaction mixturewas stirred at RT for 16 hr. The progress of the reaction was monitoredby TLC, after reaction completion reaction mixture was dissolved inethyl acetate, gave chilled water wash and followed by brine washseparate out organic layer dried over anhydrous sodium sulfate filteredand concentrated under reduced pressure to get the crude compound and itwas purified by column chromatography eluted with 1 to 5% MeOH in DCM toget6-[[4-[1-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]cyclopropyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(0.100 g, 166.80 umol, 63.97% yield, 80% purity) as yellow solid. LC-MS:(ES+)=480.6 [M+H]+.

Step-3: Synthesis of3-[6-(4-{1-[4-(1-Methyl-cyclobutanecarbonyl)-piperazin-1-yl]-cyclopropyl}-benzyl)-2-oxo-2H-benzo[cd]indol-1-yl]-piperidine-2,6-dione:To a stirred solution of6-[[4-[1-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]cyclopropyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(0.100 g, 208.50 umol) in THF (5 mL) was cooled to 0° C. then Sodiumhydride (in oil dispersion) 60% dispersion in mineral oil (57.52 mg,2.40 mmol) was added as portion-wise, after addition completion reactionmixture was stirred at 0° C. for 10 mins, later3-bromopiperidine-2,6-dione (240.21 mg, 1.25 mmol) was added andreaction mixture was stirred at RT for 10 mins, later reaction mixturewas stirred at 70° C. for 16 hr. The progress of the reaction wasmonitored by TLC after reaction completion reaction mixture was quenchedwith chilled water then extracted with ethyl acetate gave brine wash toorganic layer separate out organic layer dried over anhydrous sodiumsulfate filtered and concentrated under reduced pressure to get thecrude compound and it was purified by prep. HPLC to get3-[6-[[4-[1-[4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]cyclopropyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 263 (22 mg, 36.16 umol, 17.34% yield, 97.09% purity) as lightyellow solid. 1HNMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.32-8.30 (d,J=8 Hz, 1H), 8.07-8.05 (d, J=8 Hz, 1H), 7.80-7.76 (m, 1H), 7.41-7.39 (d,J=8 Hz, 1H), 7.24-7.22 (d, J=8 Hz, 2H), 7.14-7.08 (m, 3H), 5.45-5.41 (m,1H), 4.37 (s, 2H), 3.29 (brs, 2H), 2.97-2.90 (m, 2H), 2.79-2.72 (m, 1H),2.69-2.62 (m, 2H), 2.32 (m, 4H), 2.25-2.20 (m, 2H), 2.10-2.07 (m, 1H),1.90-1.81 (m, 1H), 1.71-1.69 (m, 2H), 1.54-1.52 (m, 1H), 1.23 (s, 3H),0.88-0.76 (m, 2H), 0.75-0.63 (m, 2H). LC-MS: (ES+)=591.3 [M+H]+.

Example 148. Synthesis of3-[6-(4-{1-[4-(2-Fluoro-phenyl)-piperazin-1-yl]-cyclopropyl}-benzyl)-2-oxo-2H-benzo[cd]indol-1-yl]-piperidine-2,6-dione(Compound 264)

Step-1: Synthesis of 1-(4-Bromo-phenyl)-cyclopropylamine: To a stirredsolution of tert-butyl N-[1-(4-bromophenyl)cyclopropyl]carbamate (3.0 g,9.61 mmol) in 1,4-Dioxane (30 mL) was added Hydrogen chloride solution4.0M in dioxane (4.0 M, 24.02 mL) at RT and reaction mixture was stirredat RT for 16 hr. The progress of the reaction was monitored by TLC,after reaction completion reaction mixture was concentrated underreduced pressure the resultant compound was triturated with ether to get1-(4-bromophenyl)cyclopropanamine (2.2 g, 8.41 mmol, 87.51% yield, 95%purity) as off-white solid. LC-MS: (ES+)=212.0, 214.0 [M+H]+.

Step-2: Synthesis of1-[1-(4-Bromo-phenyl)-cyclopropyl]-4-(toluene-4-sulfonyl)-piperazine:Taken 1-(4-bromophenyl)cyclopropanamine (3.0 g, 12.07 mmol, 021) andN,N-bis(2-chloroethyl)-4-methyl-benzenesulfonamide (3.58 g, 12.07 mmol)in sealed tube and DIPEA (23.40 g, 181.05 mmol, 31.54 mL) was added andreaction mixture was stirred at 120° C. for 24 hr. The progress of thereaction was monitored by TLC, after reaction completion reactionmixture was diluted with ethyl acetate and gave water wash and brinewash separate out organic layer dried over anhydrous sodium sulfatefiltered and concentrated under reduced pressure to get the crudecompound and it was purified by column chromatography eluted with 0 to20% ethyl acetate in Hexane to get1-[1-(4-bromophenyl)cyclopropyl]-4-(p-tolylsulfonyl)piperazine (1.5 g,3.27 mmol, 27.12% yield, 95% purity) as off-white solid. LC-MS:(ES+)=434.8, 436.8 [M+H]+.

Step-3: Synthesis of 1-[1-(4-Bromo-phenyl)-cyclopropyl]-piperazine:Hydrobromic acid, 48% (29.80 g, 368.30 mmol, 20 mL) was added to1-[1-(4-bromophenyl)cyclopropyl]-4-(p-tolylsulfonyl)piperazine (1.0 g,2.30 mmol) at RT and reaction mixture was stirred at RT for 24 hr. Theprogress of the reaction was monitored by TLC, after reaction completionreaction mixture was concentrated under reduced pressure and resultantcompound was dissolved in water and adjusted pH with sodium bi carbonateand extracted with ethyl acetate and organic layer was washed with brinesolution separate out organic layer dried over anhydrous sodium sulfatefiltered and concentrated under reduced pressure to get1-[1-(4-bromophenyl)cyclopropyl]piperazine (0.600 g, 2.09 mmol, 91.04%yield, 98% purity) as off-white solid. LC-MS: (ES+)=283.2 [M+H]+.

Step-4: Synthesis of1-[1-(4-Bromo-phenyl)-cyclopropyl]-4-(2-fluoro-phenyl)-piperazine: To astirred solution of 1-[1-(4-bromophenyl)cyclopropyl]piperazine (0.300 g,1.07 mmol) and 1-bromo-2-fluoro-benzene (560.11 mg, 3.20 mmol, 350.07uL) in Tertiary Butanol (5 mL) was added Caesium carbonate (869.03 mg,2.67 mmol) then degassed for 10 mins, later RuPhos (49.78 mg, 106.69umol) and Tris(dibenzylideneacetone)dipalladium(0) (97.70 mg, 106.69umol) was added and again degassed for 10 mins, later sealed tube wasclosed with Teflon cap and stirred at 90° C. for 16 hrs. The progress ofthe reaction was monitored by TLC, after reaction completion reactionmixture was diluted with ethyl acetate and filtered through celite bedand all solvent was mixed and concentrated under reduced pressure to getthe crude compound and it was purified by column chromatography elutedwith 0 to 30% ethyl acetate in Hexane to get1-[1-(4-bromophenyl)cyclopropyl]-4-(2-fluorophenyl)piperazine (0.160 g,409.30 umol, 38.36% yield, 96% purity) as light yellow liquid. LC-MS:(ES+)=375.1, 377.2 [M+H]+.

Step-5: Synthesis of1-(2-Fluoro-phenyl)-4-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-piperazine:To a stirred solution of1-[1-(4-bromophenyl)cyclopropyl]-4-(2-fluorophenyl)piperazine (0.160 g,426.35 umol) in 1,4-Dioxane (5 mL) was added4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(129.92 mg, 511.62 umol) in a sealed tube and Potassium acetate (104.61mg, 1.07 mmol, 66.63 uL) was added and degassed for 10 mins, later[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (34.82 mg, 42.64 umol) was added and again degassedfor 10 mins, after degassing reaction mixture was closed with Teflon capand reaction mixture was stirred at 90° C. for 16 hr. The progress ofthe reaction was monitored by TLC after reaction completion reactionmixture was diluted with ethyl acetate and filtered through celite bedand the solvent was concentrated under reduced pressure to get the crudecompound and it was purified by column chromatography eluted with 0 to30% ethyl acetate in Hexane to get1-(2-fluorophenyl)-4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]piperazine(0.100 g, 224.94 umol, 52.76% yield, 95% purity) as brown solid. LC-MS:(ES+)=423.4 [M+H]+.

Step-6: Synthesis of6-(4-{1-[4-(2-Fluoro-phenyl)-piperazin-1-yl]-cyclopropyl}-benzyl)-1-(4-methoxy-benzyl)-1H-benzo[cd]indol-2-one:To a stirred solution of6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (0.080g, 236.83 umol) and1-(2-fluorophenyl)-4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]piperazine(100.02 mg, 236.83 umol) in a mixture of Toluene (4 mL) and Ethanol (2mL) was added Potassium phosphate (125.68 mg, 592.07 umol) in a sealedtube at RT and degassed for 10 mins, later Tri(o-tolyl)phosphine (14.42mg, 47.37 umol) and Tris(dibenzylideneacetone)dipalladium(0) (21.69 mg,23.68 umol) was added and again degassed for 10 mins, after degassedreaction mixture was closed with Teflon cap and stirred at 90° C. for 16hr. The progress of the reaction was monitored by TLC after reactioncompletion reaction mixture was filtered through celite bed and bed waswashed twice with ethyl acetate all organic solvent was mixed andconcentrated under reduced pressure to get the crude compound. The crudecompound was purified by column chromatography eluted with 0 to 40%ethyl acetate in hexane to get6-(4-{1-[4-(2-Fluoro-phenyl)-piperazin-1-yl]-cyclopropyl}-benzyl)-1-(4-methoxy-benzyl)-1H-benzo[cd]indol-2-oneas light yellow solid. LC-MS: (ES+)=598.1 [M+H]+.

Step-7: Synthesis of6-(4-{1-[4-(2-Fluoro-phenyl)-piperazin-1-yl]-cyclopropyl}-benzyl)-1H-benzo[cd]indol-2-one:To a stirred solution of6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]cyclopropyl]phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(0.100 g, 167.30 umol) in Trifluoroacetic acid (0.5 mL) was addedTriflicacid (125.54 mg, 836.51 umol, 73.42 uL) at RT and reactionmixture was stirred at RT for 16 hr. The progress of the reaction wasmonitored by TLC after reaction completion reaction mixture was quenchedwith chilled water and extracted with ethyl acetate, separate outorganic layer and the aqueous layer was basified with sodium bicarbonateand extracted with ethyl acetate, gave brine wash to the organic layer,separate out organic layer dried over anhydrous sodium sulfate filteredand concentrated under reduced pressure to get the6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]cyclopropyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(0.060 g, 113.07 umol, 67.59% yield, 90% purity) as yellow solid. LC-MS:(ES+)=478.3 [M+H]+.

Step-8: Synthesis of3-[6-(4-{1-[4-(2-Fluoro-phenyl)-piperazin-1-yl]-cyclopropyl}-benzyl)-2-oxo-2H-benzo[cd]indol-1-yl]-piperidine-2,6-dione:6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]cyclopropyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(0.060 g, 125.64 umol) was dissolved in THF (5 mL) then cooled to 0° C.,later Sodium hydride (in oil dispersion) 60% dispersion in mineral oil(50.25 mg, 1.26 mmol, 60% purity) was added portion-wise at 0° C. afteraddition completion reaction mixture was stirred at 0° C. for 30 mins,later 3-bromopiperidine-2,6-dione (120.62 mg, 628.18 umol) was added andreaction mixture was stirred at RT for 1 hr, later reaction mixture wasstirred at 70° C. for 6 hr. The progress of the reaction was monitoredby TLC after reaction completion reaction mixture was quenched carefullywith chilled water and extracted with ethyl acetate gave brine wash toorganic layer, separate out organic layer dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to get thecrude compound and it was purified by column chromatography eluted with10 to 60% ethyl acetate in Hexane to get product and further it waspurified by Prep-HPLC to get3-[6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]cyclopropyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 264 (0.020 g, 32.62 umol, 25.96% yield, 96% purity) as yellowsolid. 1HNMR (400 MHz, MeOD-d6): δ 8.25-8.23 (d, J=8 Hz, 1H), 8.05-8.04(d, J=4 Hz, 1H), 7.77-7.73 (m, 1H), 7.34-7.32 (d, J=8 Hz, 1H), 7.23 (m,4H), 7.02-6.90 (m, 5H), 5.42-5.38 (m, 1H), 4.57 (s, 1H), 4.43 (m, 2H),2.96-2.92 (m, 5H), 2.83-2.78 (m, 2H), 2.65 (m, 4H), 2.2 (m, 1H),0.93-0.91 (m, 2H) 0.79-0.78 (m, 2H). LC-MS: (ES+)=589.2 [M+H]+.

Example 149. Synthesis of3-(6-((1-(1-(3-methyl-3-azabicyclo[3.1.1]heptane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 265)

Step-1: Synthesis of tert-butyl1-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate:To a stirred solution of3-[2-oxo-6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione(0.120 g, 250.02 umol, 021) in DMF (2 mL) was added3-tert-butoxycarbonyl-3-azabicyclo[3.1.1]heptane-5-carboxylic acid(60.33 mg, 250.02 umol) then HATU (285.20 mg, 750.07 umol) was added andfollowed by N,N-Diisopropylethylamine (161.57 mg, 1.25 mmol, 217.75 uL)N,N-Diisopropylethylamine (161.57 mg, 1.25 mmol, 217.75 uL) was addedand reaction mixture was stirred at RT for 16 hr. The progress of thereaction was monitored by TLC after reaction completion reaction mixturewas diluted with ethyl acetate gave water wash and followed by brinewash separate out organic layer dried over anhydrous sodium sulfatefiltered and concentrated under reduced pressure to get the crudecompound and it was purified by column chromatography eluting with 1 to5% MeOH in DCM to get tert-butyl5-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carbonyl]-3-azabicyclo[3.1.1]heptane-3-carboxylate(0.040 g, 58.79 umol, 23.51% yield, 98% purity) as yellow solid. 1HNMR(400 MHz, DMSO-d6): δ 11.11 (S, 1H), 8.38-8.36 (d, J=8 Hz, 1H),8.09-8.07 (d, J=8 Hz, 1H), 7.84-7.81 (m, 1H), 7.59-7.57 (d, J=8 Hz, 1H),7.36-7.35 (d, J=4 Hz, 1H), 7.32 (s, 1H), 7.08-7.06 (d, J=8 Hz, 1H),5.45-5.41 (m, 1H), 4.33-4.28 (m, 2H), 4.18 (s, 2H), 3.82 (m, 1H),3.48-3.37 (m, 4H), 3.08 (m, 1H), 2.94-2.90 (m, 1H), 2.77-2.75 (m, 1H),2.73-2.62 (m, 2H), 2.25-2.22 (m, 3H), 2.09-2.06 (m, 1H), 1.92 (m, 2H),1.65 (m, 4H), 1.41 (s, 9H). LC-MS: (ES+)=667.5 [M+H]+.

Step-2: Synthesis of3-(6-((1-(1-(3-azabicyclo[3.1.1]heptane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To a stirred solution of tert-butyl5-[4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carbonyl]-3-azabicyclo[3.1.1]heptane-3-carboxylate(0.060 g, 89.99 umol) in 1,4-Dioxane (2 mL) was added Hydrogen chloridesolution 4.0M in dioxane (4.0 M, 337.45 uL) at RT then reaction mixturewas stirred at RT for 16 hr. The progress of the reaction was monitoredby TLC, after reaction completion reaction mixture was concentratedunder reduced pressure then resultant compound was triturated withdiethyl ether to get3-[6-[[1-[1-(3-azabicyclo[3.1.1]heptane-5-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(0.060 g, 78.76 umol, 87.52% yield, 95% purity) as light yellow solid.LC-MS: (ES+)=567.2 [M+H]+.

Step-3: Synthesis of3-(6-((1-(1-(3-methyl-3-azabicyclo[3.1.1]heptane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To a stirred solution of3-[6-[[1-[1-(3-azabicyclo[3.1.1]heptane-5-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(0.060 g, 105.89 umol) in Acetonitrile (5 mL) was added Formaldehyde,37% w/w aq. soln., (105.89 umol, 2.0 mL) and followed by Formic Acid(2.44 g, 53.01 mmol, 2.0 mL) was added and the reaction mixture wasstirred at 90° C. for 16 hr. The progress of the reaction was monitoredby TLC, after reaction completion reaction mixture was concentratedunder reduced pressure then resultant compound was dissolved in waterand pH was adjusted to 8 with sodium bicarbonate then extracted withethyl acetate gave brine wash, separate out organic layer dried overanhydrous sodium sulfate filtered and concentrated under reducedpressure to get the crude compound and it was purified by Prep-HPLC toget3-[6-[[1-[1-(3-methyl-3-azabicyclo[3.1.1]heptane-5-carbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 265 (20 mg, 33.75 umol, 31.88% yield, 98% purity) as yellowsolid. 1HNMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.38-8.36 (d, J=8 Hz,1H), 8.09-8.07 (d, J=8 Hz, 1H), 7.84-7.81 (m, 1H), 7.59 (s, 1H), 7.59(s, 1H), 7.36-7.34 (d, J=8 Hz, 1H), 7.31 (s, 1H), 5.45-5.41 (m, 1H),4.32-4.26 (m, 2H), 4.18 (s, 1H), 3.77-3.74 (m, 1H), 3.06 (m, 1H),2.97-2.94 (m, 1H), 2.76-2.73 (m, 2H), 2.72-2.63 (m, 4H), 2.28 (s, 3H),2.12-2.05 (m, 4H), 1.93-1.88 (m, 3H), 1.80-1.65 (m, 4H). LC-MS:(ES+)=581.3 [M+H]+.

Example 150. Synthesis of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-hydroxy-methyl]pyrazol-1-yl]piperidine-1-carboxylate(Compound 266)

Step-1: Synthesis of tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate:To the stirred solution of 6-bromo-1H-benzo[cd]indol-2-one (1) (6.48 g,26.13 mmol) in THF (100 mL) was added Phenyllithium, typically 1.9M indi-n-butyl ether (1.8 M, 14.52 mL) at −78° C. and the reaction wasstirred at the same temperature for 30 minutes followed by the additionof Butyllithium (2.00 M, 14.37 mL) at −78° C. The temperature was thenraised to −40° C. and was stirred at the same temperature for 30minutes. The temperature was again lowered to −78° C. and tert-butyl4-(4-formylpyrazol-1-yl)piperidine-1-carboxylate (2) (7.3 g, 26.13 mmol)in THF (40 mL) was added and the reaction mixture was allowed to warm toroom temperature and was stirred for 16 hr. After completion of thereaction (monitored by TLC) the reaction mixture was quenched withsaturated ammonium chloride solution and extracted with EtOAc. Theorganic part was then washed with water, brine, dried over sodiumsulfate and concentrated under reduced pressure. The crude thus obtainedwas purified by combiflash (Gradient: 0-1% MeOH in DCM) to affordtert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate(3) (6.1 g, 43.20% yield) as yellow solid; LC MS: ES+ 449.5.

Step-2: Synthesis of tert-butyl4-[4-[[tert-butyl(diphenyl)silyl]oxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate:To a stirred solution of tert-butyl4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate(3) (250.0 mg, 557.40 umol) in DMF (2 mL) were added Imidazole (113.84mg, 1.67 mmol) followed by the addition ofTert-Butylchlorodiphenylsilane (229.81 mg, 836.10 umol, 214.78 uL) at 0°C. and the reaction mixture was stirred at room temperature for 16hours. TLC and LC MS were checked which showed unreacted SM beingpresent along with the desired product. The reaction mixture was thendiluted with EtOAc, washed with water and the organic fraction wasseparated. It was then dried over anhydrous sodium sulphate andconcentrated under reduced pressure. Crude thus obtained was purified byflash chromatography (Gradient: 0-5% MeOH in DCM) to afford tert-butyl4-[4-[[tert-butyl(diphenyl)silyl]oxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate(4) (140.0 mg, 36.31% yield) as yellow solid; LC MS: ES− 685.5.

Step-3: Synthesis of tert-butyl4-[4-[[tert-butyl(diphenyl)silyl]oxy-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate:To a cooled solution of4-[4-[[tert-butyl(diphenyl)silyl]oxy-(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]piperidine-1-carboxylate(4) (165.0 mg, 240.21 umol) in DMF (1 mL), Sodium hydride (60%dispersion in mineral oil) (43.23 mg, 1.08 mmol) was added portion wiseand the reaction mixture was heated at 70° C. for 1 hour followed by theaddition of 3-bromopiperidine-2,6-dione (115.30 mg, 600.51 umol) and thereaction was continued at 70° C. for 16 hours. TLC was checked whichshowed incomplete consumption of the starting material along with theformation of the desired spot. The reaction mixture was diluted withethyl acetate, washed with water and the organic fraction was separated.It was then dried over anhydrous sodium sulphate and evaporated. Crudethus obtained was purified by Prep TLC plate 30% ethyl acetate-DCM toafford tert-butyl4-[4-[[tert-butyl(diphenyl)silyl]oxy-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate(5) (75.0 mg, 35.21% yield) as yellow solid; LC MS: ES+ 542.5.

Step-4: Synthesis of3-[6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]-hydroxy-methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of tert-butyl4-[4-[[tert-butyl(diphenyl)silyl]oxy-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]piperidine-1-carboxylate(5) (70.0 mg, 87.72 umol) in Dioxane (1 mL) was added Hydrochloric acidin dioxane (87.72 umol, 5 mL) and the reaction mixture was stirred atroom temperature for 2 hours. After completion of the reaction(monitored by TLC) the reaction mixture was concentrated under reducedpressure and was triturated with ether and pentane to afford3-[6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]-hydroxy-methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione,Hydrochloride salt (6) (40.0 mg, 50.10% yield) as yellow solid. LC MS:ES+ 460.4.

Step-5: Synthesis of tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-hydroxy-methyl]pyrazol-1-yl]piperidine-1-carboxylate:To a stirred solution of3-[6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]-hydroxy-methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(6) (40.00 mg, 80.65 umol) in DCM (6 mL) was added Triethylamine (24.48mg, 241.96 umol, 33.72 uL) at 0° C. followed by the addition ofDi-tert-butyl dicarbonate (26.40 mg, 120.98 umol, 27.76 uL) and thereaction was stirred at room temperature for 16 hours. After completionof the reaction (monitored by TLC) the reaction mixture was diluted withethyl acetate, washed with water and the organic fraction was separated.It was then dried over anhydrous sodium sulphate and concentrated underreduced pressure. The crude thus obtained was purified by preparativeTLC plate in 4% MeOH-DCM to afford tert-butyl4-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]-hydroxy-methyl]pyrazol-1-yl]piperidine-1-carboxylateCompound 266 (14.0 mg, 30.76% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.42-8.39 (m, 1H), 8.05 (d, J=6.92 Hz, 1H),7.76 (t, J=7.6 Hz, 1H), 7.60-7.57 (m, 2H), 7.31 (s, 1H), 7.11 (d, J=7.28Hz, 1H), 6.26-6.23 (m, 1H), 5.86-5.84 (m, 1H), 5.45-5.42 (m, 1H),4.25-4.23 (m, 1H), 3.99-3.96 (m, 2H), 2.96-2.95 (m, 1H), 2.81-2.74 (m,3H), 2.67-2.63 (m, 1H), 2.10-2.07 (m, 1H), 1.89-1.86 (m, 2H), 1.69-1.66(m, 2H), 1.39 (s, 9H); LC MS: ES− 558.4.

Example 151. Synthesis of3-[24-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-28-oxo-31,34-diazatricyclododeca-,2(22),7(23),21(25),24(31)-pentaen-34-yl]piperidine-2,6-dione(Compound 267)

Step 1: Synthesis of 4-bromoisoquinoline 2-oxide (2): To a stirredsolution of 4-bromoisoquinoline 1 (50 g, 240.32 mmol) in DCM (300 mL) at0° C. portion wise 3-chlorobenzenecarboperoxoic acid (82.94 g, 480.64mmol) was added. The combined reaction mixture was stirred 15 mins at 0°C. and then stirred for 2 h at room temperature. After completion of thereaction 30% IPA DCM solution was added. 20g Sodium Sulfite was added toquench excess MCPBA. Sodium Sulfite was filtered off through sinteredflask and the filtrate (30% IPA DCM solution) was washed with saturatedbicarbonate solution for 3 times followed by water. The organic layerwas dried over sodium sulfate, filtered and concentrated under reducedpressure to afford 4-bromo-2-oxido-isoquinolin-2-ium 2 (46.5 g, 94.40mmol, 78.44% yield, 90% purity) as off-white solid. LCMS: ES+ 224.31.

Step 2: Synthesis of ethyl(2Z)-2-(4-bromoisoquinolin-1(2H)-ylidene)-2-cyanoacetate (3): To astirred suspension of 4-bromo-2-oxido-isoquinolin-2-ium 2 (46 g, 205.31mmol) in DCM (200 mL) ethyl 2-cyanoacetate (27.87 g, 246.37 mmol, 26.29mL), Pyridine (19.49 g, 246.37 mmol, 19.93 mL) were added and thecombined reaction mixture was cooled to 0° C. Acetic anhydride (25.15 g,246.37 mmol, 23.29 mL) was added to the reaction mixture dropwise. Thereaction mixture was stirred at 0-5° C. for 12 hours. It was thenstirred at room temperature for 2 days. After completion of the reaction(monitored by LCMS), the reaction mixture was evaporated under reducedpressure, the solid was diluted with DCM, washed with water and brinesolution. The organic fraction was separated, dried over anhydroussodium sulphate, filtered and evaporated under reduced pressure toobtain the crude compound. The crude compound was purified by columnchromatography using DCM to afford ethyl(2Z)-2-(4-bromo-2H-isoquinolin-1-ylidene)-2-cyano-acetate 3 (38 g,113.11 mmol, 55.09% yield, 95% purity) as yellow solid. LC MS: ES+319.1.

Step 3: Synthesis of 4-bromo-1-methylisoquinoline (4): To ethyl(2Z)-2-(4-bromo-2H-isoquinolin-1-ylidene)-2-cyano-acetate 3 (38 g,113.11 mmol), 35% H₂SO₄ solution (400 mL) was added and the combinedreaction mixture was refluxed at 110° C. for 48-72 hours. Aftercompletion of the reaction (monitored by LCMS), the reaction mixture waspoured into crushed ice and quenched with 20% NaOH solution, dilutedwith dichloromethane, washed with water, bicarbonate solution and brine.The organic fraction was separated, dried over anhydrous sodium sulphateand evaporated under reduced pressure to obtain4-bromo-1-methyl-isoquinoline 4 (19 g, 84.70 mmol, 99% purity) asoff-white solid. LC MS: ES+ 222.3.

Step 4: Synthesis of 4-bromo-1-methyl-5-nitroisoquinoline (5): To astirred solution of 4-bromo-1-methyl-isoquinoline 4 (19 g, 85.55 mmol)in Sulfuric Acid (80 mL) portion wise Potassium nitrate, 99% (9.51 g,94.11 mmol, 4.51 mL) was added. The combine reaction mixture was heatedat 65° C. for 3 h. The reaction progression was monitored through TLC.After consumption of the starting material, the reaction mixture waspoured in ice cold water and the acid solution was neutralized withpotassium carbonate or 20% NaOH solution. After neutralization theaqueous layer was extracted with ethyl acetate thrice and the combinedorganic layer was dried over sodium sulfate and filtered. The organiclayer was concentrated under reduced pressure and crude product waswashed with pentane to remove nonpolar impurities. After washing, theproduct was dried under reduced pressure to afford4-bromo-1-methyl-5-nitro-isoquinoline 5 (17 g, 63.02 mmol, 73.66% yield,99% purity). LC MS: ES+ 266.9.

Step 5: Synthesis of 4-bromo-1-methylisoquinolin-5-amine (6): To astirred solution of 4-bromo-1-methyl-5-nitro-isoquinoline 5 (17 g, 63.65mmol) in Ethanol (50 mL) Water (50 mL), Iron powder (17.77 g, 318.26mmol, 2.26 mL) and dichlorocalcium; dihydrate (14.04 g, 95.48 mmol) wereadded and the combined reaction mixture was heated at 90° C. for 3 h.The reaction progression was monitored through TLC. After completion ofthe reaction, the reaction mixture was passed through a whatmann filterpaper to remove Fe powder and CaCl₂). Ethyl acetate was added to thefiltrate and the organic layer was washed with water and the organiclayer was dried over sodium sulfate and filtered. The organic part wasconcentrated under reduced pressure. The crude product was washed withpentane to remove the non-polar impurities and dried under reducedpressure to afford 4-bromo-1-methyl-isoquinolin-5-amine 6 (14 g, 58.46mmol, 91.84% yield, 99% purity). LC MS: ES+ 237.1.

Step 6: Synthesis of 4-bromo-1-methylisoquinoline-5-carbonitrile (7): Toa stirred solution of cuprous; cyanide (5.29 g, 59.05 mmol) intert-butyl nitrite (12.18 g, 118.09 mmol, 14.05 mL) a solution of4-bromo-1-methyl-isoquinolin-5-amine 6 (14 g, 59.05 mmol) in DMSO (85mL) was added drop wise. The combined reaction mixture was stirred for16 h at 65° C. After completion of the reaction, the reaction mixturewas filtered through a whatmann filter paper and the filtrate was washedwith cold water and brine. The organic layer was dried over sodiumsulfate and filtered. The organic layer was concentrated under reducedpressure and the crude product was purified through flash chromatographyusing 30% ethylacetate and hexane to afford4-bromo-1-methyl-isoquinoline-5-carbonitrile 7 (2.5 g, 10.163 mmol,17.21% yield, 98% purity). LC MS: ES+ 247.01.

Step 7: Synthesis of5-methyl-11,12-diazatricyclododeca-1(3),2(6),4(8),5(11),7(9)-pentaen-10-one(8): A mixture of 4-bromo-1-methyl-isoquinoline-5-carbonitrile 7 (2.5 g,10.12 mmol), Potassium hydroxide, flake, 85% (1.42 g, 25.29 mmol, 695.67uL) and Tertiary Butanol (20 mL) was heated at 80° C. for 18 h in a oilbath. The progression of the reaction was monitored through TLC. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. Ethyl acetate was added to the reaction mixture andthe organic layer was washed with water. Organic part was dried oversodium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified through flash column chromatography using 3%methanol DCM as eluent to afford5-methyl-11,12-diazatricyclododeca-1(3),2(6),4(8),5(11),7(9)-pentaen-10-one8 (1 g, 5.32 mmol, 52.59% yield, 98% purity) as yellow solid. LC MS: ES+185.11.

Step 8: Synthesis of1-(4-methoxybenzyl)-6-methylpyrrolo[2,3,4-de]isoquinolin-2(1H)-one (9):To a stirred solution of5-methyl-11,12-diazatricyclododeca-1(3),2(6),4(8),5(11),7(9)-pentaen-10-one8 (500 mg, 2.71 mmol) in DMF (4.0 mL) Sodium hydride (in oil dispersion)60% dispersion in mineral oil (156.02 mg, 4.07 mmol, 60% purity) wasadded at 0° C. The reaction mixture was stirred for 30 mins at the sametemperature. 1-(chloromethyl)-4-methoxy-benzene (510.15 mg, 3.26 mmol,425.12 uL) was added to the reaction mixture and the combined reactionmixture was stirred for 30 min at room temperature. The reactionprogression was monitored through TLC. After consumption of the startingmaterial, ethylacetate was added to the reaction mixture. The organiclayer was washed with cold water followed by brine solution to removeDMF. The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified bycombi-flash to afford20-[(4-methoxyphenyl)methyl]-11-methyl-19,20-diazatricyclododeca-2(4),3(14),9(16),11(19),15(17)-pentaen-18-one9 (515 mg, 1.64 mmol, 60.47% yield, 97% purity) as yellowish solid. LCMS: ES+ 305.3.

Step 9: Synthesis of6-(chloromethyl)-1-(4-methoxybenzyl)pyrrolo[2,3,4-de]isoquinolin-2(1H)-one(10): To20-[(4-methoxyphenyl)methyl]-11-methyl-19,20-diazatricyclododeca-2,4(15),9(16),11(19),14(17)-pentaen-18-one9 (200 mg, 657.16 umol) in Chloroform (15.0 mL) at reflux was added1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (122.18 mg, 525.72 umol,59.03 uL) in portions, and the mixture was heated at reflux 15 mins.After cooling, the mixture was filtered, and the filtrate was dilutedwith chloroform, washed with brine, dried(MgSO₄), and evaporated to getthe crude which was purified by prep TLC (as 5% Ethylacetate/Hexaneeluent) to give16-(chloromethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diazatricyclododeca-1,3(14),8(15),13(17),16(19)-pentaen-18-one10 (190 mg, 476.70 umol, 72.54% yield, 85% purity); LC MS: ES+ 339.3.

Step 10: Synthesis of6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-1-(4methoxybenzyl)pyrrolo[2,3,4-de]isoquinolin-2(1H)-one (12): To a welldegassed solution of16-(chloromethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diazatricyclododeca-1,3(14),8(15),13(17),16(19)-pentaen-18-one10 (190 mg, 560.82 umol) and8-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-1-oxa-8-azaspiro[4.5]decane11 (240.45 mg, 672.99 umol) inethanol (2.0 mL)-Toluene (4.0 mL),Potassium phosphate tribasic anhydrous (238.09 mg, 1.12 mmol) was addedfollowed by the addition Tri-o-Tolyl phosphine (27.31 mg, 89.73 umol)and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (41.08 mg, 44.87umol). The resulting mixture was then heated at 90° C. for 12 hours.After completion of reaction (as monitored by LCMS), the reactionmixture was filtered through a bed of celite, washed with Ethyl acetate(100 mL). The combined filtrate was washed with water (3×20 mL) andbrine (2×15 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure. Crude mass was purified by column chromatography(silica, gradient: 0-5% MeOH in DCM) to obtain36-[(4-methoxyphenyl)methyl]-30-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-34,36-diazatricyclododeca-1,3(28),12(29),27(31),30(34)-pentaen-32-one 12 (40 mg, 67.46 umol, 12.03%yield, 90% purity) as yellow solid and stored in a round bottom glass atrt. LC MS: ES+ 534.5.

Step 10a: Synthesis of8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-oxa-8-azaspiro[4.5]decane(11): To a stirred solution of 1-oxa-8-azaspiro[4.5]decane (1.0 g, 7.08mmol) in ACN (15 mL), N-ethyl-N-isopropyl-propan-2-amine (1.10 g, 8.50mmol, 1.48 mL) was added. After 10 min2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.52g, 8.50 mmol) was added to the solution and stirred for 4 hours at roomtemperature. Saturated NaHCO₃ solution was added and the organic partwas extracted with ethyl acetate followed by brine washing. Organicsolution was dried over Na₂SO₄, concentrated under vacuum to get aresidue which was purified by column chromatography using 5% MeOH in DCMto afford8-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-1-oxa-8-azaspiro[4.5]decane11 (0.67 g, 1.69 mmol, 23.83% yield, 90% purity).

Step 11: Synthesis of6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)pyrrolo[2,3,4-de]isoquinolin-2(1H)-one(13):36-[(4-methoxyphenyl)methyl]-30-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-34,36-diazatricyclododeca-1,3(28),12(29),27(31),30(34)-pentaen-32-one12 (50 mg, 93.69 umol) in TFA (3.0 mL), Triflic acid (211.31 mg, 1.41mmol, 123.57 uL) dropwise. The reaction mixture was stirred at 25° C.for 16 hours. After completion of reaction, volatiles were evaporatedand quenched with saturated sodium bicarbonate solution. Aqueous partwas extracted with ethyl acetate (40 mL), washed with water followed bybrine. The organic part was dried over sodium sulphate and concentratedto afford crude22-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-26,27-diazatricyclododeca-,2(20),7(21),19(23),22(26)-pentaen-24-one13 (30 mg, 72.55 umol, 77.43% yield) as brown solid. Crude was carriedforward in the next step. LC MS: ES+ 414.5.

Step 12: Synthesis of3-[24-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-28-oxo-31,34-diazatricyclododeca-,2(22),7(23),21(25),24(31)-pentaen-34-yl]piperidine-2,6-dione:To a cooled solution of22-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-26,27-diazatricyclododeca-,2(20),7(21),19(23),22(26)-pentaen-24-one13 (30.00 mg, 72.55 umol) in dry THF (250 mL), Sodium hydride (in oildispersion) 60% dispersion in mineral oil (27.80 mg, 725.50 umol, 60%purity) was added portion wise, maintaining the temp <5° C. Once theaddition is over, the resultant mixture was stirred for 15 minutes atRT. Then the reaction mixture was again cooled to 0° C. and3-bromopiperidine-2,6-dione 14 (69.65 mg, 362.75 umol) was added to itportion wise. After complete addition, resulting solution was heated at70° C. 1 hour. After completion (evidenced from TLC), the reactionmixture was cooled to 0° C. and quenched with the addition of ice cooledwater. Aqueous part was extracted with ethyl acetate (3×50 mL). Combinedorganics was separated, dried over sodium sulfate and concentrated underreduced pressure. Crude mass was purified by flash chromatography(silica, gradient: 0%-2.5% MeOH in DCM) to afford3-[24-[[4-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)phenyl]methyl]-28-oxo-31,34-diazatricyclododeca-,2(22),7(23),21(25),24(31)-pentaen-34-yl]piperidine-2,6-dioneCompound 267 (10 mg, 17.87 umol, 24.63% yield, 93.75% purity) as yellowsolid. ¹H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.56 (d, J=8.2 Hz,1H), 8.31 (d, J=7.0 Hz, 1H), 8.21 (s, 1H), 7.94 (t, J=7.56 Hz, 1H),7.29-7.27 (m, 2H), 7.18-7.17 (m, 2H), 5.48-5.46 (m, 1H), 4.56 (s, 2H),3.65 (t, J=6.68 Hz, 2H), 3.35-3.31 (m, 2H), 2.98-2.92 (m, 1H), 2.82-2.78(m, 1H), 2.67-2.63 (m, 1H), 2.36-2.27 (m, 4H), 2.13-2.10 (m, 1H),1.82-1.78 (m, 2H), 1.60-1.56 (m, 2H), 1.50-1.45 (m, 4H); LC MS: ES+525.2.

Example 152. Synthesis of3-[6-[[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 268)

Step 1: Synthesis of methyl 6-(chloromethyl)pyridine-3-carboxylate (2):methyl 6-(hydroxymethyl)pyridine-3-carboxylate (1) (2.0 g, 11.96 mmol)was added portion wise to thionyl chloride (28.47 g, 239.29 mmol, 17.36mL) in ice cold condition and stirred the reaction mixture for 30 min atrt. After completion of reaction, the reaction mixture was evaporatedand quenched with sodium bicarbonate solution. Aqueous part wasextracted with ethyl acetate (50 mL). The organic layer was washed withwater followed by brine, dried over sodium sulphate and concentratedunder reduced pressure. The crude material was purified by columnchromatography by 20% ethyl acetate in hexane to afford the desiredcompound methyl 6-(chloromethyl)pyridine-3-carboxylate (2) (1.15 g, 5.74mmol, 47.95% yield, 93% purity) as yellowish solid. LC MS: ES+ 186.16.

Step 2: Synthesis of [6-(chloromethyl)-3-pyridyl]methanol (3): To thestirred solution of -(chloromethyl)pyridine-3-carboxylate (2) (1.15 g,6.20 mmol) in THF (20.0 mL), Diisobutylaluminum hydride (14.10 g, 24.78mmol, 20.11 mL) was added drop wise at −78° C. and stirred for 30minutes at rt under N₂ atmosphere. After complete consumption, asevidenced from TLC, reaction mass was diluted with ethyl acetate (50 mL)and quenched 20% Sodium potassium tertrate solution. Organic phase wasseparated, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford [6-(chloromethyl)-3-pyridyl]methanol (3) (938 mg,5.65 mmol, 91.26% yield, 95% purity) as reddish gummy solid which wascarried forward to the next step without any further purification. LCMS: ES+ 157.9.

Step 3: Synthesis of[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methanol (5): To astirred solution 1-oxa-8-azaspiro[4.5]decane; hydrochloride (4) (550 mg,3.10 mmol) in dry grade acetone (10 mL) was added Potassium carbonate,anhydrous, 99% (1.28g, 9.29 mmol) at RT and the resultant reactionmixture was heated at 50° C. for 20 minutes.[6-(chloromethyl)-3-pyridyl]methanol (3) (975.72 mg, 6.19 mmol, 69.39mL) was then added to the reaction mixture and heating was continued for4 hours. After completion of reaction (monitored by TLC and LCMS),volatiles were removed under vacuum and the solid thus obtained wastaken in Ethyl acetate (50 mL), washed with water (20 mL) and Brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure. Crude mass was purified by column chromatography (silica,gradient: 1-5% MeOH in DCM) to afford[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methanol (5) (600mg, 2.06 mmol, 66.49% yield, 90% purity) as colorless sticky solid. LCMS: ES+ 263.5.

Step 4: Synthesis of8-[[5-(chloromethyl)-2-pyridyl]methyl]-1-oxa-8-azaspiro[4.5]decane(6):To the stirred solution of[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methanol (5) (600mg, 2.29 mmol) in DCM (5.0 mL), thionmyl chloride (544.18 mg, 4.57 mmol,331.82 uL) was added drop wise at 0° C. and stirred for 30 minutes atrt. After completion of reaction, monitored by TLC, volatiles wereremoved under reduced pressure. Solid mass was redissolved inethylacetate (30 mL) and quenched with saturated sodium bicarbonatesolution. Organic phase was separated, dried over anhydrous sodiumsulfate and concentrated to afford crude8-[[5-(chloromethyl)-2-pyridyl]methyl]-1-oxa-8-azaspiro[4.5]decane (6)(550 mg, 1.86 mmol, 81.36% yield, 95% purity) as brown sticky solidwhich directly used in the next step without any purification. LC MS:ES+ 281.1.

Step 5: Synthesis of6-[[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methyl]-1H-benzo[cd]indol-2-one(8): To a well degassed solution of8-[[5-(chloromethyl)-2-pyridyl]methyl]-1-oxa-8-azaspiro[4.5]decane (6)(450 mg, 1.60 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(7) (945.99 mg, 3.21 mmol) in ethanol (2.0 mL)-Toluene (4.0 mL),Potassium phosphate tribasic anhydrous (1.02 g, 4.81 mmol) was addedfollowed by the addition Tri-o-Tolyl phosphine (97.56 mg, 320.52 umol)and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (146.75 mg,160.26 umol). The resulting mixture was then heated at 90° C. for 12hours. After completion of reaction (as monitored by LCMS), the reactionmixture was filtered through a bed of celite, washed with Ethyl acetate(100 mL). The combined filtrate was washed with water (3×20 mL) andbrine (2×15 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure. Crude mass was purified by column chromatography(silica, gradient: 0-5% MeOH in DCM) to obtain6-[[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methyl]-1H-benzo[cd]indol-2-one(8) (90 mg, 180.65 umol, 11.27% yield, 83% purity) as yellow solid andstored in a round bottom glass at rt. LC MS: ES+ 414.3.

Step 6: Synthesis of3-[6-[[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a cooled solution of6-[[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methyl]-1H-benzo[cd]indol-2-one(8) (86.00 mg, 207.98 umol) in dry THF (5.0 mL), Sodium hydride (in oildispersion) 60% dispersion in mineral oil (79.69 mg, 2.08 mmol, 60%purity) was added portion wise, maintaining the temp <5° C. Once theaddition is over, the resultant mixture was stirred for 15 minutes atRT. Then the reaction mixture was again cooled to 0° C. and3-bromopiperidine-2,6-dione (9) (199.67 mg, 1.04 mmol) was added to itportion wise. After complete addition, resulting solution was heated at70° C. 1 hour. After completion (evidenced from TLC), the reactionmixture was cooled to 0° C. and quenched with the addition of ice cooledwater. Aqueous part was extracted with ethyl acetate (3×50 mL). Combinedorganics was separated, dried over sodium sulfate and concentrated underreduced pressure. Crude mass was purified by flash chromatography(silica, gradient: 0 TO 2.5% MeOH in DCM) to afford Racemic3-[6-[[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 268 (33 mg, 62.03 umol, 29.83% yield, 98.61% purity) as yellowsolid. ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.52 (br s, 1H), 8.37(d, J=8.24 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.82 (t, J=7.64 Hz, 1H),7.60-7.58 (m, 1H), 7.43 (d, J=7.32 Hz, 1H), 7.30 (d, J=7.96 Hz, 1H),7.11 (d, J=7.32 Hz, 1H), 5.44 (dd, J=12.8, 5.08 Hz, 1H), 4.40 (s, 2H),3.66 (t, J=6.68 Hz, 2H), 3.49 (br s, 2H), 2.95-2.93 (m, 1H), 2.77-2.73(m, 1H), 2.66-2.62 (m, 1H), 2.42-2.41 (m, 2H), 2.32 (br m, 2H),2.10-2.07 (m, 1H), 1.82-1.77 (m, 2H), 1.61-1.57 (m, 2H), 1.50 (br s,4H); LC MS: ES+ 525.68.

Example 153. Synthesis of3-[6-[[6-(morpholinomethyl)-3-pyridyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 269)

Step 1: Synthesis of[6-(1-oxa-8-azaspiro[4.5]decan-8-ylmethyl)-3-pyridyl]methanol (5): To astirred solution of morpholine (2) (650 mg, 7.46 mmol, 652.61 uL) in drygrade acetone (10.0 mL) was added potassium carbonate (1.55 g, 11.19mmol, 675.45 uL) at RT and the resultant reaction mixture was heated at60° C. for 60 minutes. [6-(chloromethyl)-3-pyridyl]methanol (1) (587.91mg, 3.73 mmol, 70.75 mL) was then added to the reaction mixture andheating was continued for 16 hours. After completion of reaction(monitored by TLC and LCMS), volatiles were removed under vacuum and thesolid thus obtained was taken in Ethyl acetate (70 mL), washed withwater (×3) and Brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. Crude mass was purified by columnchromatography (silica, gradient: 10-30% Ethyl acetate in Hexane) toafford [6-(morpholinomethyl)-3-pyridyl]methanol (3) (550 mg, 2.51 mmol,67.25% yield, 95% purity) as light yellowish solid. LC MS: ES+ 209.46.

Step 2: Synthesis of 4-[[5-(chloromethyl)-2-pyridyl]methyl]morpholine(6): To a stirred solution of [6-(morpholinomethyl)-3-pyridyl]methanol(3) (276 mg, 1.33 mmol) in DCM (5.0 mL) was cooled to 0° C. then netthionyl chloride (315.34 mg, 2.65 mmol, 192.28 uL) was added dropwise tothe reaction mix and stirred the reaction mix at rt for 1 hr. Check TLCshows complete consumption of SM, then the reaction mix was evaporatedunder reduced pressure to remove excess thionyl chloride. After that thereaction mix was quenched with Saturated sodiumbi carbonate solution andextracted with Ethylacetate (3×25 mL). The organic portion was washedwith brine solution., dried over Na₂SO₄ and evaporated under rotavaporto get the crude compound4-[[5-(chloromethyl)-2-pyridyl]methyl]morpholine (4) (288 mg, 1.26 mmol,94.90% yield, 99% purity) as brown gum. LC MS: ES+ 227.1.

Step 3: Synthesis of6-[[6-(morpholinomethyl)-3-pyridyl]methyl]-1H-benzo[cd]indol-2-one (8):To a well degassed solution of4-[[5-(chloromethyl)-2-pyridyl]methyl]morpholine (4) (288 mg, 1.27 mmol)and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one(5) (749.89 mg, 2.54 mmol) inethanol (2.0 mL)-Toluene (4.0 mL),Potassium phosphate tribasic anhydrous (809.00 mg, 3.81 mmol) was addedfollowed by the addition Tri-o-Tolyl phosphine (77.33 mg, 254.08 umol)and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (116.33 mg,127.04 umol). The resulting mixture was then heated at 90° C. for 12hours. After completion of reaction (as monitored by LCMS), the reactionmixture was filtered through a bed of celite, washed with Ethyl acetate(100 mL). The combined filtrate was washed with water (3×20 mL) andbrine (2×15 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure. Crude mass was purified by column chromatography(silica, gradient: 0-5% MeOH in DCM) to obtain6-[[6-(morpholinomethyl)-3-pyridyl]methyl]-1H-benzo[cd]indol-2-one (6)(65 mg, 126.59 umol, 9.96% yield, 70% purity) as yellow solid and storedin a round bottom glass at rt. LC MS: ES+ 360.4.

Step 4: Synthesis of afford3-[6-[[6-(morpholinomethyl)-3-pyridyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a cooled solution of6[[6-(morpholinomethyl)-3-pyridyl]methyl]-1H-benzo[cd]indol-2-one (6)(50.00 mg, 139.11 umol) in dry THF (5.0 mL), Sodium hydride (in oildispersion) 60% dispersion in mineral oil (53.30 mg, 1.39 mmol, 60%purity) was added portion wise, maintaining the temp <5° C. Once theaddition is over, the resultant mixture was stirred for 15 minutes atRT. Then the reaction mixture was again cooled to 0° C. and3-bromopiperidine-2,6-dione (7) (133.56 mg, 695.56 umol) was added to itportion wise. After complete addition, resulting solution was heated at70° C. 1 hour. After completion (evidenced from TLC), the reactionmixture was cooled to 0° C. and quenched with the addition of ice cooledwater. Aqueous part was extracted with ethyl acetate (3×50 mL). Combinedorganics was separated, dried over sodium sulfate and concentrated underreduced pressure. Crude mass was purified by flash chromatography(silica, gradient: 0%-2.5% MeOH in DCM) to afford3-[6-[[6-(morpholinomethyl)-3-pyridyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 269 (15.0 mg, 29.24 umol, 21.02% yield, 91.72% purity) asyellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.53 (s, 1H),8.37 (d, J=8.28 Hz, 1H), 8.08 (d, J=6.96 Hz, 1H), 7.82 (t, J=7.64 Hz,1H), 7.61-7.59 (m, 1H), 7.42 (d, J=7.44 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H),7.11 (d, J=7.28 Hz, 1H), 5.44 (dd, J=12.76, 5.24 Hz, 1H), 4.40 (s, 2H),3.54-3.50 (m, 6H), 2.95-2.94 (m, 1H), 2.77-2.73 (m, 1H), 2.66-2.62 (m,1H), 2.34 (br s, 4H), 2.10-2.07 (m, 1H); LC MS: ES+ 471.58.

Example 154. Synthesis of3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 270)

Step-1: Synthesis of 4-bromo-1-tetrahydropyran-2-yl-pyrazole: To astirred solution of 4-bromo-1H-pyrazole (1) (10 g, 68.04 mmol) in3,4-dihydro-2H-pyran (8.58 g, 102.06 mmol, 9.27 mL), Trifluoroaceticacid (387.90 mg, 3.40 mmol, 262.10 uL) was added drop wise under coolingcondition and the resultant reaction mixture was at 80° C. for 16 h.After completion of the reaction (monitored by TLC) the reaction mixturewas diluted with DCM and washed with 1(M) NaOH solution. The organicpart was then dried over Na₂SO₄ and concentrated under reduced pressure.The crude thus obtained was purified by combi-flash column (Gradient:0-10% EtOAc in Hexane) to afford 4-bromo-1-tetrahydropyran-2-yl-pyrazole(2) (14 g, 88.15% yield) as yellow gum; LC MS: ES+ 231.1.

Step-2: Synthesis of1-benzyl-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-3,6-dihydro-2H-pyridine:To a stirred solution of 4-bromo-1-tetrahydropyran-2-yl-pyrazole (2)(700 mg, 3.03 mmol) in Water (4.0 mL) and DMF (16.0 mL) were addedSodium carbonate (642.11 mg, 6.06 mmol),1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine(3) (1.09 g, 3.63 mmol) and the resultant reaction mixture was degassedwith Argon for 15 min. Then cyclopentyl(diphenyl)phosphane; dichloromethane; di chloropalladium; iron (247.37 mg, 302.91 umol) wasadded and stirred the reaction mixture was stirred at 100° C. for 16 hin a sealed tube. After completion of the reaction (monitored by TLC)the reaction mixture was diluted with EtOAc and washed with water,brine, dried over Na₂SO₄ and concentrated under reduced pressure. Thecrude thus obtained was purified by combi-flash column (Gradient: 0-20%EtOAc in Hexane) to afford1-benzyl-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-3,6-dihydro-2H-pyridine(4) (230 mg, 22.07% yield) as colourless gum; LC MS: ES+ 324.4.

Step-3: Synthesis of 4-(1-tetrahydropyran-2-ylpyrazol-4-yl)piperidine:To a stirred solution of1-benzyl-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-3,6-dihydro-2H-pyridine(4) (230 mg, 711.13 umol) in Ethylacetate (5.0 mL) and Ethanol (5.0 mL)Argon gas was purged for 10 mins. Then Palladium on carbon (20% w/w,151.36 mg, 1.42 mmol) was added and the reaction mixture was stirredunder Hydrogen atmosphere (Balloon) for 16 h. After completion of thereaction (monitored by TLC) the reaction mixture was filtered throughcelite pad and washed with 10% MeOH in DCM. The collected filtrate wasconcentrated under reduced pressure to afford4-(1-tetrahydropyran-2-ylpyrazol-4-yl)piperidine (5) (150 mg, 76.19%yield) as light yellow gum.

Step-4: Synthesis of(1-methylcyclobutyl)-[4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-1-piperidyl]methanone:To a stirred solution of 1-methylcyclobutanecarboxylic acid (6) (194.26mg, 1.70 mmol) in DMF (2.0 mL) was addedN-ethyl-N-isopropyl-propan-2-amine (439.91 mg, 3.40 mmol, 592.87 uL) andthe resultant reaction mixture was stirred at RT for 5 mins, then HATU(647.12 mg, 1.70 mmol) was added and the reaction was stirred foranother 5 mins. After that a solution of4-(1-tetrahydropyran-2-ylpyrazol-4-yl)piperidine (5) (267 mg, 1.13 mmol)in DMF (2.0 mL) was added and the reaction mixture was stirred at RT for16 h. After completion of the reaction (monitored by TLC) the reactionmixture was diluted with EtOAc and washed with cold NaHCO₃, dried overNa₂SO₄ and concentrated under reduced pressure. The crude thus obtainedwas purified by combi-flash column (Gradient: 0-30% EtOAc in Hexane) toafford(1-methylcyclobutyl)-[4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-1-piperidyl]methanone(7) (100 mg, 26.06% yield) as yellow sticky solid; LC MS: ES+ 332.4.

Step-5: Synthesis of(1-methylcyclobutyl)-[4-(1H-pyrazol-4-yl)-1-piperidyl]methanone;hydrochloride: To a stirred solution of(1-methylcyclobutyl)-[4-(1-tetrahydropyran-2-ylpyrazol-4-yl)-1-piperidyl]methanone(7) (100 mg, 301.70 umol) in dioxane (2 ml) was added Hydrogen chloridesolution 4.0 M in dioxane (5 mL) and the resultant reaction mixture wasstirred at RT for 16 h. After completion of the reaction (monitored byTLC) the reaction mixture was concentrated to dryness and trituratedwith ether to afford(1-methylcyclobutyl)-[4-(1H-pyrazol-4-yl)-1-piperidyl]methanone;hydrochloride (8) (90 mg, 74.52% yield) as yellow solid.

Step-6: Synthesis of1-[(4-methoxyphenyl)methyl]-6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]benzo[cd]indol-2-one:To a stirred solution of(1-methylcyclobutyl)-[4-(1H-pyrazol-4-yl)-1-piperidyl]methanone (8)(200.00 mg, 808.62 umol) and6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (int-A)(273.15 mg, 808.62 umol) in DMF (2 mL) was added Cesium carbonate(526.93 mg, 1.62 mmol) and the reaction mixture was heated at 90° C. for16 h. After completion of the reaction (monitored by TLC) the reactionmixture was diluted with EtOAc and washed with water and brine, driedover sodium sulphate and concentrated. The crude thus obtained waspurified by Combiflash column (Gradient: 0-2% MeOH in DCM) to afford1-[(4-methoxyphenyl)methyl]-6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]benzo[cd]indol-2-one(9) (300 mg, 60.86% yield) as light yellow solid. LC MS: ES+ 549.7.

Step-7: Synthesis of6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of compound1-[(4-methoxyphenyl)methyl]-6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]benzo[cd]indol-2-one(9) (500.00 mg, 911.29 umol) in TFA (4 mL) was addedtrifluoromethanesulfonic acid (683.83 mg, 4.56 mmol, 399.90 uL) undercooling condition and the resultant reaction mixture was stirred at roomtemperature for 16 h. After completion of the reaction (monitored byTLC) the reaction mixture was quenched with saturated bicarbonatesolution and extracted with ethyl acetate. The organic layer was thendried over sodium sulphate and concentrated under reduced pressure. Thecrude thus obtained was purified by combiflash chromatography (Gradient:0-3% MeOH in DCM) to afford6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one(10) (350 mg, 80.66% yield) as light yellow solid; LC MS: ES+ 429.4.

Step-8: Synthesis of3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of compound6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-1H-benzo[cd]indol-2-one(10) (175 mg, 408.38 umol) in DMF (3 mL) was added Sodium hydride (inoil dispersion) 60% dispersion in mineral oil (23.47 mg, 1.02 mmol)under cooling condition and then the reaction mixture was stirred at 70°C. for 1 hour. Then 3-bromopiperidine-2,6-dione (11) (78.41 mg, 408.38umol) was added and stirred at 70° C. for another 2 hr. Again3-bromopiperidine-2,6-dione (11) (78.41 mg, 408.38 umol) was added andthe reaction was continued at 70° C. for 16 h. After completion of thereaction (monitored by TLC) the reaction mixture was quenched with icewater and extracted with EtOAc. The organic part was then dried oversodium sulphate and concentrated. The crude thus obtained was purifiedby Prep TLC Plate (5% MeOH in DCM) to afford3-[6-[[4-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-1-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 270 (20 mg, 8.17% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.43 (d, J=8.32 Hz, 1H), 8.10 (d, J=6.96 Hz,1H), 7.85 (t, J=7.64 Hz, 1H), 7.67 (s, 1H), 7.45 (d, J=7.52 Hz, 1H),7.32 (s, 1H), 7.12 (d, J=7.4 Hz, 1H), 5.67 (s, 2H), 5.47-5.42 (m, 1H),4.35-4.31 (m, 1H), 3.52-3.48 (m, 1H), 2.99-2.90 (m, 2H), 2.76-2.72 (m,1H), 2.66-2.63 (m, 2H), 2.41-2.34 (m, 2H), 2.09-2.07 (m, 1H), 1.92-1.82(m, 1H), 1.82-1.76 (m, 5H), 1.60-1.57 (m, 1H), 1.40-1.42 (m, 5H); LC MS:ES− 538.5.

Example 155. Synthesis of3-(6-((1-(4-methyl-1-(4-methyl-1-(pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 271)

Step-1: Synthesis of methyl4-methyl-1-(pyridin-2-yl)piperidine-4-carboxylate: To a stirred solutionof methyl 1-chloro-4-methyl-piperidine-4-carboxylate 2 (1.15 g, 5.94mmol, 575.47 uL) in DMF (1 mL) in a sealed tube was added Triethylamine(601.55 mg, 5.94 mmol, 828.59 uL). It was stirred at RT for 10 minutes.2-chloropyridine 1 (450 mg, 3.96 mmol, 371.90 uL) was added to thereaction mixture. It was heated at 100° C. for 16 h. It was diluted withwater, extracted with ethyl acetate, dried over sodium sulfate,concentrated under reduced pressure. It was purified by combiflasheluting at 25% ethyl acetate in hexane to afford methyl4-methyl-1-(2-pyridyl)piperidine-4-carboxylate 3 (95 mg, 352.76 umol,8.90% yield, 87% purity) as colourless liquid. LC MS: ES+ 235.3.

Step-2: Synthesis of 4-methyl-1-(pyridin-2-yl)piperidine-4-carboxylicacid: To the stirred solution of methyl 4-methyl-1-(2-pyridyl)piperidine-4-carboxylate 3 (85 mg, 362.79 umol) in THF (4 mL) and Water(1 mL) was added Lithium hydroxide monohydrate, 98% (30.45 mg, 725.59umol, 20.16 uL). It was stirred at RT for 16 hours. It was quenched with1N HCl to nutralise the solution and was extracted with ethylacetatefour times. Combined organic part was washed with brine, dried oversodium sulfate, concentrated under reduced pressure to afford4-methyl-1-(2-pyridyl)piperidine-4-carboxylic acid 4 (35 mg, 143.01umol, 39.42% yield, 90% purity) as a white solid.

Step-3: Synthesis of3-(6-((1-(4-methyl-1-(4-methyl-1-(pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To the stirred solution of3-[6-[[1-(1-chloro-4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione5 (50.0 mg, 101.22 umol) in DMF (1 mL) was addedN,N-Diisopropylethylamine (39.24 mg, 303.65 umol, 52.89 uL) in coldcondition followed by the addition4-methyl-1-(2-pyridyl)piperidine-4-carboxylic acid 4 (22.29 mg, 101.22umol, 13.94 uL) and HATU (57.73 mg, 151.83 umol) and the reaction wascontinued at room temperature for 16 hours. TLC and LCMS were checkedwhich showed formation of the desired spot. The reaction mixture wasdiluted with ethyl acetate, washed with sodium bicarbonate solution,water and the organic fraction was separated. It was dried overanhydrous sodium sulphate and evaporated under reduced pressure toobtain the crude which was purified by preparative TLC plate methoddeveloping the plate in 3% MeOH-DCM to afford3-[6-[[1-[4-methyl-1-[4-methyl-1-(2-pyridyl)piperidine-4-carbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 271 (11 mg, 16.54 umol, 16.34% yield, 99.22% purity) as yellowsolid. 11.11 (s, 1H), 8.39 (d, J=8.28 Hz, 1H), 8.10-8.07 (m, 2H),7.85-7.78 (m, 2H), 7.50-7.46 (m, 1H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.24Hz, 1H), 6.75 (d, J=8.64 Hz, 1H), 6.58-6.56 (m, 1H), 5.45-5.42 (m, 1H),4.21 (s, 2H), 3.75-3.71 (m, 4H), 3.31-3.26 (m, 3H), 2.94-2.91 (m, 1H),2.77-2.73 (m, 1H), 2.66-2.62 (m, 1H), 2.57-2.50 (m, 2H), 2.40-2.32 (m,1H), 2.10-2.17 (m, 3H), 1.76-1.72 (m, 2H), 1.48-1.46 (m, 2H), 1.36-1.33(m, 3H), 1.23 (s, 3H); LC MS: ES+ 660.3.

Example 156. Synthesis of3-(6-((1-(4-methyl-1-(1-(pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 272)

Step-1: Synthesis of methyl 1-(pyridin-2-yl)piperidine-4-carboxylate: Tothe stirred solution of 2-chloropyridine 1 (483.73 mg, 4.26 mmol, 399.78uL) in a sealed tube was added methyl piperidine-4-carboxylate 2 (610mg, 4.26 mmol, 575.47 uL). It was heated at 100° C. for 16 hours. It wasdiluted with ethyl acetate, washed with saturated sodium bicarbonatesolution, dried over sodium sulfate, concentrated under reducedpressure. It was purified by combiflash eluting at 20% ethyl acetate inhexane to afford methyl 1-(2-pyridyl)piperidine-4-carboxylate 3 (210 mg,905.72 umol, 21.26% yield, 95% purity) as colourless liquid. LC MS: ES+221.3.

Step-2: Synthesis of 1-(pyridin-2-yl)piperidine-4-carboxylic acid: To astirred solution of methyl 1-(2-pyridyl)piperidine-4-carboxylate 3 (200mg, 907.99 umol) in THF (8 mL) and Water (2 mL) was added Lithiumhydroxide monohydrate, 98% (114.30 mg, 2.72 mmol, 75.69 uL). It wasstirred at RT for 16 h. It was quenched with 1N HCl to nutralise thesolution and was extracted with ethylacetate four times. Combinedorganic part was washed with brine, dried over sodium sulfate,concentrated under reduced pressure to afford1-(2-pyridyl)piperidine-4-carboxylic acid 4 (130 mg, 598.82 umol, 65.95%yield, 95% purity) as a white solid. 12.21 (s, 1H), 8.09-8.07 (m, 1H),7.51-7.47 (m, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.60-6.57 (m, 1H), 4.18-4.15(m, 2H), 2.94-2.87 (m, 2H), 2.46-2.45 (m, 1H), 1.86-1.82 (m, 2H),1.55-1.45 (m, 2H).

Step-3: Synthesis of3-(6-((1-(4-methyl-1-(1-(pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To the stirred solution of3-[6-[[1-(1-chloro-4-methyl-4-piperidyl)pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione5 (50.0 mg, 101.22 umol) in DMF (1 mL) was addedN,N-Diisopropylethylamine (39.24 mg, 303.65 umol, 52.89 uL) in coldcondition followed by the addition 1-(2-pyridyl)piperidine-4-carboxylicacid 4 (20.88 mg, 101.22 umol, 13.94 uL) and HATU (57.73 mg, 151.83umol) and the reaction was continued at room temperature for 16 hours.TLC (5% methanol in dichloromethane) and LCMS were checked which showedformation of the desired spot. The reaction mixture was diluted withethyl acetate, washed with sodium bicarbonate solution, water and theorganic fraction was separated. It was dried over anhydrous sodiumsulphate and evaporated under reduced pressure to obtain the crude whichwas purified by preparative TLC (3% methanol in dichloromethane) toafford3-[6-[[1-[4-methyl-1-[1-(2-pyridyl)piperidine-4-carbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 272 (27 mg, 41.59 umol, 41.09% yield, 99.46% purity) as yellowsolid. 11.11 (s, 1H), 8.39 (d, J=7.84 Hz, 1H), 8.09-8.08 (m, 2H),7.85-7.79 (m, 2H), 7.51-7.47 (m, 1H), 7.36-7.34 (m, 2H), 7.07 (d, J=7.08Hz, 1H), 6.80 (d, J=7.92 Hz, 1H), 6.59-6.56 (m, 1H), 5.45-5.42 (m, 1H),4.29-4.27 (m, 2H), 4.21 (s, 2H), 3.69-3.65 (m, 2H), 3.13-3.10 (m, 1H),2.94-2.91 (m, 4H), 2.76-2.63 (m, 2H), 2.37-2.32 (m, 1H), 2.25-2.23 (m,1H), 2.08-2.07 (m, 2H), 1.80-1.48 (m, 6H), 1.36 (s, 3H); LC MS: ES+646.3.

Example 157. Synthesis of3-(6-(4-(morpholinomethyl)phenoxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 273)

Step-1: Synthesis of6-hydroxy-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one: To a stirredsolution of1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indole-6-carbaldehyde (1)(200 mg, 630.24 umol) in DCM (10 mL), mCPBA (108.76 mg, 630.24 umol) wasadded at rt and the reaction mixture warmed to 40° C. and stirred for 12hr. After completion of the reaction (monitored by TLC), the reactionmixture was cooled at 0° C. and 2 M NH3-MeOH (3.15 mmol) was added dropwise until red wine color exists and stirred for 2 hr at same temp.After that, the reaction mixture was diluted with EtOAc (20 mL) andquenched with saturated sodium bicarbonate solution and the layers wereseparated. The organic part was then dried over sodium sulfate andconcentrated. The crude thus obtained was purified by columnchromatography (100-200 silica, Gradient: 0-50% EtOAc in Hexane) toobtain sticky 6-hydroxy-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(2) (145 mg, 68.57% yield) as yellow solid. LC MS: ES+ 306.

Step-2: Synthesis of1-[(4-methoxyphenyl)methyl]-6-[4-(morpholinomethyl)phenoxy]benzo[cd]indol-2-one:To the Oxygen purged solution of6-hydroxy-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (2) (1 g, 3.28mmol) and [4-(morpholinomethyl)phenyl]boronic acid (3) (724.01 mg, 3.28mmol) in Methanol (5 mL) cupriosulfanylcopper (26.06 mg, 163.76 umol)and N,N,N′,N′-tetramethylethane-1,2-diamine (380.61 mg, 3.28 mmol,491.11 uL) were added and the reaction was stirred at RT for 16 h. Aftercompletion of the reaction (monitored by TLC) the reaction mixture wasfiltered through celite pad and washed with EtOAc. The collectedfiltrate was further washed with water (3 times) and brine, dried oversodium sulfate and concentrated under reduced pressure. The crude thusobtained was purified by column chromatography (100-200 Silica;Gradient: 0-30% EtOAc in DCM) to afford1-[(4-methoxyphenyl)methyl]-6-[4-(morpholinomethyl)phenoxy]benzo[cd]indol-2-one(4) (180 mg, 10.86% yield) as yellow solid; LC MS: ES+ 481.4.

Step-3: Synthesis of6-[4-(morpholinomethyl)phenoxy]-1H-benzo[cd]indol-2-one: To a stirredsolution of1-[(4-methoxyphenyl)methyl]-6-[4-(morpholinomethyl)phenoxy]benzo[cd]indol-2-one(4) (180 mg, 374.57 umol) in TFA (2 mL), Trifluoromethanesulfonic acid(562.15 mg, 3.75 mmol, 328.74 uL) were added and the resultant reactionmixture was stirred at RT stirred for 12 hr. After completion of thereaction (monitored by TLC) the reaction mixture was quenched withsaturated sodium bicarbonate solution and extracted with ethyl acetate(Twice)). The combined organic part was then dried over sodium sulfateand concentrated under reduced pressure. The crude thus obtained waspurified by column chromatography (100-200 silica; Gradient 0-2% MeOH inDCM) to afford 6-[4-(morpholinomethyl)phenoxy]-1H-benzo[cd]indol-2-one(5) (80 mg, 55.71% yield) as yellow solid; LC MS: ES+ 361.1.

Step-4: Synthesis of3-(6-(4-(morpholinomethyl)phenoxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To a stirred solution of6-[4-(morpholinomethyl)phenoxy]-1H-benzo[cd]indol-2-one (5) (80 mg,221.97 umol) in dry DMF (2 mL), Sodium hydride (in oil dispersion) 60%dispersion in mineral oil (17.01 mg, 443.95 umol, 60% purity) was addedat 0° C. and the resultant reaction mixture was heated at 70° C. for 1hr. After that, 3-bromopiperidine-2,6-dione (6) (42.62 mg, 221.97 umol)was added and the reaction was continued for 12 hr at 70° C. Reactionwas monitored by TLC and LCMS which showed unreacted SM being present.Again 3-bromopiperidine-2,6-dione (6) (42.62 mg, 221.97 umol) was addedto the reaction mixture and heating was continued for another 6 hr. Thereaction was then quenched with chilled water/ammonium chloride solutionand extracted with ethyl acetate (3 times). The combined organic partwas then dried over sodium sulfate and concentrated under reducedpressure. The crude thus obtained was purified by Prep-TLC Plate (30%EtOAc in DCM) to afford3-[6-[4-(morpholinomethyl)phenoxy]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 273 (5 mg, 4.41% yield) as yellow solid. 1H NMR (400 MHz,DMSO-d6) δ 11.15 (s, 1H), 8.17-8.13 (m, 2H), 7.87-7.83 (m, 1H), 7.30 (d,J=7.88 Hz, 2H), 7.12-7.10 (m, 1H), 7.05-7.00 (m, 3H), 5.49-5.45 (m, 1H),3.56 (br s, 4H), 3.42 (s, 2H), 2.96-2.95 (m, 2H), 2.67-2.62 (m, 1H),2.32 (br s, 4H), 2.10-2.07 (m, 1H); LC MS: ES+ 472.5.

Example 158. Synthesis of3-[6-[[1-[4-[(1-methylcyclobutyl)methyl]-4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 274) and3-[6-[[1-[4-[(1-methylcyclobutyl)methyl]-4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 275)

Step-1: Synthesis of tert-butyl 5-hydroxyspiro[2.5]octane-8-carboxylate:To a stirred solution of tert-butyl 5-oxospiro[2.5]octane-8-carboxylate(1) (1 g, 4.46 mmol) in Methanol (5 mL) was added Sodium Borohydride(202.39 mg, 5.35 mmol, 189.15 uL) under cooling condition and thereaction mass was stirred at Rt for 4 h. After completion of thereaction (monitored by TLC) the reaction mass was concentrated underreduced pressure and was diluted with cold water. The aqueous part wasthen extracted with EtOAc and the organic layer was further washed withbrine, dried over sodium sulphate and concentrated to afford tert-butyl5-hydroxyspiro[2.5]octane-8-carboxylate (2) (1 g, 94.15% yield) asyellow solid. 1HNMR (400 MHz, DMSO-d6): □ 4.67-4.66 (d, J=4.8 Hz, 1H),3.76-3.68 (m, 2H), 2.84-2.80 (m, 2H), 1.76-1.72 (m, 1H), 1.57-1.52 (m,1H), 1.39 (s, 9H), 1.25-1.16 (m, 2H), 0.98-0.96 (m, 1H), 0.76-0.70 (m,1H), 0.45-0.40 (m, 2H).

Step-2: Synthesis of tert-butyl5-methylsulfonyloxyspiro[2.5]octane-8-carboxylate: To a stirred solutionof tert-butyl 5-hydroxyspiro[2.5]octane-8-carboxylate (2) (1 g, 4.42mmol) in DCM (20 mL) was added Triethylamine (894.26 mg, 8.84 mmol, 1.23mL) under cooling condition and the reaction mass was stirred for 10minutes. Then Mesyl Chloride (607.40 mg, 5.30 mmol, 410.41 uL) was addedand the resultant reaction mixture was stirred at RT for 16 hours. Aftercompletion of the reaction (monitored by TLC) the reaction mixture wasdiluted with DCM and washed with water, saturated Sodium bicarbonatesolution, brine and dried over sodium sulphate and concentrated toafford tert-butyl 5-methylsulfonyloxyspiro[2.5]octane-8-carboxylate (3)(1.2 g, 84.75% yield) as colourless gum. 1HNMR (400 MHz, DMSO-d6): □4.90-4.85 (m, 1H), 3.71-3.67 (m, 1H), 3.19 (s, 3H), 3.11-3.06 (m, 1H),1.97-1.96 (m, 1H), 1.77-1.72 (m, 1H), 1.65-1.62 (m, 1H), 1.55-1.51 (m,1H), 1.40 (s, 9H), 1.17 (t, 1H), 0.98-0.095 (m, 1H), 0.82-0.76 (m, 1H),0.65-0.60 (m, 2H).

Step-3: Synthesis of tert-butyl7-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate:To a stirred solution of1-[(4-methoxyphenyl)methyl]-7-(1H-pyrazol-4-ylmethyl)-2H-benzo[de]quinolin-3-one(4) (1.2 g, 3.13 mmol) and tert-butyl7-methylsulfonyloxy-4-azaspiro[2.5]octane-4-carboxylate (3) (1.15 g,3.76 mmol) in DMF (15 mL) was added Cesium carbonate (2.04 g, 6.26 mmol)and the resultant reaction mixture was stirred at 100° C. for 16 hours.After completion of the reaction (monitored by TLC) the reaction mixturewas diluted with EtOAc washed with water and brine, dried over sodiumsulfate and concentrated. The crude thus obtained was purified bycombiflash chromatography (Gradient: 0-30% EtOAc in Hexane) to affordtert-butyl7-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate(5) (1 g, 48.39% yield) as light yellow solid; LC MS: ES+ 579.8.

Step-4, 4a & 4b: Synthesis of tert-butyl7-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylateand tert-butyl 7-[4-[(2-oxo-1H-benzoyl)methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate: To astirred solution of tert-butyl7-[4-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate(5) (1 g, 1.73 mmol) in TFA (5 mL) was added trifluoromethanesulfonicacid (2.59 g, 17.28 mmol, 1.52 mL) and the resultant reaction mixturewas stirred at RT for 16 hours. After completion of the reaction(monitored by TLC and LC MS) the reaction mass was concentrated andcrude thus obtained was diluted with DCM (10 mL) and TEA (874.29 mg,8.64 mmol, 1.20 mL) was added to it under cooling condition followed bythe addition of tert-butoxycarbonyl tert-butyl carbonate (565.71 mg,2.59 mmol, 594.86 uL). The resultant reaction mixture was then stirredat Rt for 16 hours. After completion of the reaction (monitored by TLCand LC MS) the reaction mixture was diluted with DCM and washed withwater, brine, dried over sodium sulphate and concentrated. The crudethus obtained was purified by combi-flash (Gradient: 0-30% EtOAc inHexane) to afford Racemic7-[4-(2-Oxo-1,2-dihydro-benzo[cd]indol-6-ylmethyl)-pyrazol-1-yl]-4-aza-spiro[2.5]octane-4-carboxylicacid tert-butyl ester (7) (600 mg). This Racemic was separated to itsenantiomers by SFC Chiral Prep to afford tert-butyl7-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate(7a) (250 mg, 31.55% yield, eluted as first Fraction) and tert-butyl7-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate(7b) (250 mg, 31.55% yield, eluted as second fraction) as yellow solid.LC MS ES+ 459.61.

Step-5a: Synthesis of tert-butyl7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate:To a cooled solution of tert-butyl7-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate(7a) (200 mg, 436.16 umol) in dry THF (10 mL), Sodium hydride (60%dispersion in mineral oil) (167.12 mg, 4.36 mmol) was added portionwise, maintaining the temp <5° C. Once the addition is over, theresultant mixture was stirred for 15 minutes at RT. Then the reactionmixture was again cooled to 0° C. and 3-bromopiperidine-2,6-dione (8)(83.75 mg, 436.16 umol) was added to it portion wise. After completeaddition, resulting solution was heated at 70° C. for 1 hour. Aftercompletion (evidenced from TLC), the reaction mixture was cooled to 0°C. and quenched with the addition of ice cooled water. Aqueous part wasextracted with ethyl acetate (3 times). Combined organics was separated,dried over sodium sulfate and concentrated under reduced pressure. Crudemass was purified by combiflash column (gradient: 0-30% EtOAc in DCM) toafford tert-butyl7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate(9a) (200 mg, 75.67% yield) as yellow solid. LC MS ES+ 570.2.

Step-6a: Synthesis of[7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octan-4-yl]2,2,2-trifluoroacetate:To a stirred solution of tert-butyl7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate(9a) (200 mg, 351.09 umol) in DCM (5 mL) was added TFA (600.48 mg, 5.27mmol, 405.73 uL) and the reaction mixture was stirred at RT for 4 hours.After completion of the reaction (monitored by TLC) the reaction masswas concentrated under reduced pressure and the crude thus obtained wastriturated with Ether-Pentane to afford[7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octan-4-yl]2,2,2-trifluoroacetate(10a) (200 mg, 77.58% yield) as yellow gum. LC MS ES+ 470.1. Step-7a:Synthesis of3-[6-[[1-[4-[(1-methylcyclobutyl)methyl]-4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:A solution of3-[6-[[1-[4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione;2,2,2-trifluoroaceticacid (10a) (100.00 mg, 171.36 umol) in DCE (4 mL) and Triethylamine(17.34 mg, 171.36 umol, 23.88 uL) was stirred under cooling conditionfor 15 min. To it Acetic acid (10.29 mg, 171.36 umol, 9.80 uL) and1-methylcyclobutanecarbaldehyde (11) (16.82 mg, 171.36 umol, 16.49 uL)were added and the reaction mixture was stirred at RT for 1 hour. ThenSodium cyanoborohydride (16.15 mg, 257.04 umol) was added and thereaction was allowed to stir at RT for 16 h. After completion of thereaction (monitored by TLC and LCMS), the reaction mixture was dilutedwith ethyl acetate, washed with sodium bicarbonate solution and theorganic fraction was separated. It was then dried over anhydrous sodiumsulphate and evaporated under reduced pressure to obtain the crude whichwas purified by preparative TLC plate (3% MeOH-DCM) to afford3-[6-[[1-[4-[(1-methylcyclobutyl)methyl]-4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 274 (25.0 mg, 26.44% yield) as yellow solid. 1HNMR (400 MHz,DMSO-d6): □ 11.11 (s, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.0 Hz,1H), 7.83 (t, J=7.58 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J=7.28 Hz, 1H),7.31 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.64, 5.36 Hz, 1H),4.23-4.18 (m, 3H), 2.96-2.62 (m, 6H), 2.28-2.35 (m, 2H), 2.09-2.08 (m,2H), 1.90-1.69 (m, 4H), 1.56-1.49 (m, 3H), 1.03 (m, 4H), 0.49-0.42 (m,3H), 0.35-0.33 (m, 1H); LC MS: ES+ 552.24.

Step-5b: Synthesis of tert-butyl7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate:To a cooled solution of tert-butyl7-[4-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate(7b) (250 mg, 545.16 umol) in dry THF (10 mL), Sodium hydride (60%dispersion in mineral oil) (208.9 mg, 5.45 mmol) was added portion wise,maintaining the temp<5° C. Once the addition is over, the resultantmixture was stirred for 15 minutes at RT. Then the reaction mixture wasagain cooled to 0° C. and 3-bromopiperidine-2,6-dione (8) (523 mg, 2.73mmol) was added to it portion wise. After complete addition, resultingsolution was heated at 70° C. for 1 hour. After completion (evidencedfrom TLC), the reaction mixture was cooled to 0° C. and quenched withthe addition of ice cooled water. Aqueous part was extracted with ethylacetate (3 times). Combined organics was separated, dried over sodiumsulfate and concentrated under reduced pressure. Crude mass was purifiedby combiflash column (gradient: 0-30% EtOAc in DCM) to afford tert-butyl7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate(9b) (200 mg, 61% yield) as yellow solid. LC MS ES+ 570.2.

Step-6b: Synthesis of[7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octan-4-yl]2,2,2-trifluoroacetate:To a stirred solution of tert-butyl7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate(9b) (143.14 mg, 263.32 umol) in DCM (5 mL) was added TFA (450.36 mg,3.95 mmol, 304.29 uL) and the reaction mixture was stirred at RT for 4hours. After completion of the reaction (monitored by TLC) the reactionmass was concentrated under reduced pressure and the crude thus obtainedwas triturated with Ether-Pentane to afford[7-[4-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]pyrazol-1-yl]-4-azaspiro[2.5]octan-4-yl]2,2,2-trifluoroacetate(10b) (150 mg, 72.1% yield) as yellow gum. LC MS ES+ 470.1.

Step-7b: Synthesis of3-[6-[[1-[4-[(1-methylcyclobutyl)methyl]-4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:A solution of3-[6-[[1-[4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione;2,2,2-trifluoroaceticacid (10b) (150.00 mg, 257.04 umol) in DCE (5 mL) and Triethylamine(26.01 mg, 257.04 umol, 35.83 uL) was stirred under cooling conditionfor 15 min. To it Acetic acid (10.29 mg, 171.36 umol, 9.80 uL) and1-methylcyclobutanecarbaldehyde (11) (16.82 mg, 171.36 umol, 16.49 uL)were added and the reaction mixture was stirred at RT for 1 hour. ThenSodium cyanoborohydride (16.15 mg, 257.04 umol) was added and thereaction was allowed to stir at RT for 16 h. After completion of thereaction (monitored by TLC and LCMS), the reaction mixture was dilutedwith ethyl acetate, washed with sodium bicarbonate solution and theorganic fraction was separated. It was then dried over anhydrous sodiumsulphate and evaporated under reduced pressure to obtain the crude whichwas purified by preparative TLC plate (3% MeOH-DCM) to afford3-[6-[[1-[4-[(1-methylcyclobutyl)methyl]-4-azaspiro[2.5]octan-7-yl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 275 (40 mg, 28.08% yield) as yellow solid. 1HNMR (400 MHz,DMSO-d6): 11.11 (s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.08 (d, J=7.0 Hz,1H), 7.83 (t, J=7.64 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.36 Hz, 1H),7.31 (s, 1H), 7.07 (d, J=7.28 Hz, 1H), 5.43 (dd, J=12.8, 5.2 Hz, 1H),4.25-4.23 (m, 1H), 4.18 (s, 2H), 2.94-2.62 (m, 6H), 2.28-2.23 (m, 2H),2.10-2.07 (m, 2H), 1.90-1.67 (m, 4H), 1.56-1.47 (m, 3H), 1.03 (m, 4H),0.49-0.42 (m, 3H), 0.35-0.33 (m, 1H); LC MS: ES+ 552.24.

Example 159. Synthesis of tert-butyl4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]piperidine-1-carboxylate(Compound 276)

Step-1: Synthesis of4-(2-oxo-1H-benzo[cd]indol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate:To a stirred solution of 5-(-bromo-1H-benzo[cd]indol-2-one (4 g, 16.12mmol) and and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(4.99 g, 16.12 mmol) in Dioxane (15 mL), DMF (5 mL) and water (5 mL) wasadded sodium carbonate ((6.84 g, 64.50 mmol) and thoroughly purged withargon. Xphos pd G3 (682.41 mg, 806.21 umol) was added under inertatmosphere. Resulting mixture was heated at 90° C. for 12 h. Aftercompletion, reaction mixture was diluted with ethyl acetate, filteredthrough a short pad of celite and washed with ethyl acetate. Combinedorganic part was washed with water and brine, dried over anhydroussodium sulphate, filtered and concentrated under reduced pressure. Crudemass was purified by column chromatography (50% ethyl acetate-hexane) toafford tert-butyl4-(2-oxo-1H-benzo[cd]indol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(4.5 g, 12.84 mmol, 78% yield); LC MS: ES+ 351.2.

Step-2: Synthesis of tert-butyl4-(2-oxo-1H-benzo[cd]indol-6-yl)piperidine-1-carboxylate: To a degassedsolution of4-(2-oxo-1H-benzo[cd]indol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(4.5 g, 12.84 mmol) in Ethyl acetate (30 mL) Pd/C 10% by wt (50% wet)(3.5 g, 5.50 mmol) was added. Resulting mixture was stirred at RT underhydrogen balloon pressure for 16 hours. After completion, the reactionmixture was filtered through a short pad of celite, washed with ethylacetate and concentrated under reduced pressure. Crude mass was purifiedby combiflash chromatography (50% ethylacetate in hexane) to tert-butyl4-(2-oxo-1H-benzo[cd]indol-6-yl)piperidine-1-carboxylate (2.97 g, 66%).

Step-3: Synthesis of tert-butyl4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]piperidine-1-carboxylate:To a stirred solution of 6 tert-butyl4-(2-oxo-1H-benzo[cd]indol-6-yl)piperidine-1-carboxylate (3 g, 8.51mmol) in THF (80 mL) and DMF (20 mL) was added Sodium hydride (60%dispersion in mineral oil) (3.26 g, 85.12 mmol, 60% purity) slowlyportion wise at 0° C. Resultant mixture was stirred the reaction for 30min at RT. 3-bromopiperidine-2,6-dione (8.17 g, 42.56 mmol) was thenadded to it portion wise at RT and reaction mixture was heated to 70° C.and continued for 3 h. After completion, reaction was quenched withcrushed ice extracted with ethyl acetate. Combined organic part waswashed with water and brine. Organic layer was dried with anhydroussodium sulphate, filtered and concentrated under reduced pressure. Crudemass was purified by column chromatography (70% EA-hexane) to affordtert-butyl4-[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]piperidine-1-carboxylate(2.22 g, 4.70 mmol, 55.22% yield) as yellow solid. 1H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.46 (d, J=8.3 Hz, 1H), 8.10 (d, J=6.9 Hz,1H), 7.86 (t, J=7.4 Hz, 1H), 7.37 (d, J=7.4 Hz, 1H), 7.08 (d, J=7.4 Hz,1H), 5.46-5.41 (m, 1H), 4.12 (d, J=11.2 Hz, 2H), 3.50 (t, J=11.8 Hz,1H), 2.99-2.90 (m, 3H), 2.80-2.62 (m, 2H), 2.09-2.07 (m, 1H), 1.85 (d,J=12.2 Hz, 2H), 1.67-1.59 (m, 2H), 1.43 (s, 9H); LC MS: ES+ 464.2.

Example 160. Synthesis of3-(6-benzyl-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione (Compound277)

Step-1: Synthesis of6-Benzyl-1-(4-methoxy-benzyl)-1H-benzo[cd]indol-2-one: To a stirredsolution of6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (0.500g, 1.48 mmol) and phenylboronic acid (360.95 mg, 2.96 mmol) in a mixtureof Toluene (6.5 mL) and Ethanol (3.5 mL) in a sealed tube was addedPotassium phosphate (785.47 mg, 3.70 mmol) then degassed for 10 mins,later Tris(o-tolyl)phosphine (90.10 mg, 296.03 umol) andTris(dibenzylideneacetone)dipalladium(0) (135.54 mg, 148.02 umol) wasadded and again degassed for 10 mins, after degassing reaction mixturewas closed with teflon cap and stirred at 90° C. for 16 hr. The progressof the reaction was monitored by TLC, after reaction completion reactionmixture was filtered through celite bed and bed was washed twice withethyl acetate then collected solvent was concentrated under reducedpressure to get the crude compound and it was purified by columnchromatography eluted with 10 to 30% ethyl acetate in Hexane to get6-benzyl-1-[(4-ethoxyphenyl)methyl]benzo[cd]indol-2-one (0.300 g, 774.81umol, 52.35% yield, 98% purity) as yellow solid. LC-MS: (ES+)=380.2[M+H]+.

Step-2: Synthesis of 6-Benzyl-1H-benzo[cd]indol-2-one:6-benzyl-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (0.300 g,790.62 umol) was dissolved in Trifluoroacetic acid (5 mL) and cooled to0° C. then Triflic acid (593.27 mg, 3.95 mmol, 346.94 uL) was added andreaction mixture was stirred at RT for 16 hr. The progress of thereaction was monitored by TLC, after reaction completion reactionmixture was dissolved in water and pH was adjusted with aqueous sodiumbi carbonate to 6 then extracted with ethyl acetate gave brine washseparate out organic layer dried over anhydrous sodium sulfate filteredand concentrated under reduced pressure to get the crude compound and itwas purified by column chromatography eluted with 10 to 50% ethylacetate in Hexane to get 6-benzyl-1H-benzo[cd]indol-2-one (0.190 g,718.08 umol, 90.83% yield, 98% purity) as yellow solid. LC-MS:(ES+)=260.2 [M+H]+.

Step-3: Synthesis of3-(6-benzyl-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione:6-benzyl-1H-benzo[cd]indol-2-one (0.100 g, 385.65 umol) was dissolved inTHF (10 mL) then cooled to 0° C. later Sodium hydride (in oildispersion) 60% dispersion in mineral oil (147.77 mg, 3.86 mmol, 60%purity) was added portion wise and stirred at 0° C. for 30 mins, later3-bromopiperidine-2,6-dione (370.25 mg, 1.93 mmol) was added andreaction mixture was stirred at RT for 30 mins, later stirred at 0° C.for 16 hr. The progress of the reaction was monitored by TLC, afterreaction completion reaction mixture was quenched with chilled waterthen extracted with ethyl acetate gave brine wash separate out organiclayer dried over dried over anhydrous sodium sulfate filtered andconcentrated under reduced pressure to get the crude compound and it waspurified by column chromatography eluted with 10 to 50% ethyl acetate inHexane and followed by again purified by column chromatography elutedwith 5 to 20% MeOH in DCM to get3-(6-benzyl-2-oxo-benzo[cd]indol-1-yl)piperidine-2,6-dione Compound 277(50 mg, 134.26 umol, 34.81% yield, 99.46% purity) yellow solid. 1HNMR(400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.33-8.30 (d, J=12 Hz, 1H),8.07-8.06 (d, J=4 Hz, 1H), 7.82-7.78 (m, 1H), 7.41-7.39 (d, J=8 Hz, 1H),7.29-7.24 (m, 4H), 7.17-7.15 (m, 1H) 7.11-7.09 (d, J=8 Hz, 1H),5.46-5.41 (m, 1H), 4.39 (s, 2H), 2.98-2.90 (m, 1H), 2.79-2.70 (m, 1H),2.66-2.62 (m, 1H), 2.10-2.09 (m, 1H). LC-MS: (ES+)=371.1 [M+H]+.

Example 161. Synthesis of3-[6-{[3-fluoro-4-(morpholinomethyl)phenyl]methyl}-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 278)

Step-1: Synthesis of 4-[(4-bromo-2-fluoro-phenyl)methyl]morpholine: Tostirred solution of morpholine (812 mg, 9.32 mmol, 815.26 uL) in Acetone(100 mL) was added Potassium carbonate, anhydrous, 99% (3.22 g, 23.30mmol, 1.41 mL) stirred for 10 minutes and then4-bromo-1-(bromomethyl)-2-fluoro-benzene (3.00 g, 11.18 mmol) was addedand stirred the reaction mixture at 60° C. for 8 hr. After completion ofSM, reaction mixture was concentrated under reduced pressure, thendiluted with ethyl acetate and washed with water, organic layerseparated, dried over sodium sulphate, dried under rotavaour to give thetitle compound 4-[(4-bromo-2-fluoro-phenyl)methyl]morpholine (2.5 g,92.95% yield, 95% purity) as a white solid. LC-MS: (ES+)=276.1 [M+H]+.

Step-2: Synthesis of4-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine:To a stirred solution of 4-[(4-bromo-2-fluoro-phenyl)methyl]morpholine(1 g, 3.65 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan(1.20 g, 4.74 mmol) and Potassium Acetate (895.02 mg, 9.12 mmol, 570.07uL) in 1,4-Dioxane (15 mL) was purged with Argon for 10 minutes thencyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(297.90 mg, 364.79 umol) was added and heated the reaction mixture for14 hr at 90° C. The reaction mixture was diluted with ethyl acetate andwashed with water followed by brine. The organic layer was dried oversodium sulphate and concentrated. The crude material was purified bysilica gel column chromatography by 15% ethyl acetate in hexane toafford4-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine(1 g, 72.54% yield, 85% Purity) as yellow sticky gum. LCMS (ES+)=322.4[M+H]+.

Step-3: Synthesis of6-{[3-fluoro-4-(morpholinomethyl)phenyl]methyl}-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one:To a stirred solution of4-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine4 (350 mg, 1.09 mmol) intoluene (10 mL) and Ethanol (5 mL) was added6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one 5(552.14 mg, 1.63 mmol), tripotassium phosphate (578.27 mg, 2.72 mmol).The reaction mixture was degassed with argon for 15 minutes. Thentris-o-tolylphosphane (66.33 mg, 217.94 umol) andTris(Dibenzylideneacetone)dipalladium (0) (99.78 mg, 108.97 umol) wasadded and again purged for 5 minutes. The reaction mixture was stirredand heated at 100° C. for 14 hr. The reaction mixture was evaporated anddiluted with ethyl acetate and washed with water, followed by brine. Theorganic layer was dried over sodium sulphate and concentrated and thecrude material was purified by silica gel column chromatography by15-20% ethyl acetate in hexane to afford the6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(450 mg, 81.08% yield, 97.5% Purity) as yellowish solid. LCMS(ES+)=497.5 [M+H]+.

Step-4: Synthesis of6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one:6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(450 mg, 906.21 umol) in TFA (10 mL) in cooled condition was addedTriflic acid (2.04 g, 13.59 mmol, 1.19 mL) dropwise. The reactionmixture was stirred at 25° C. for 16 hr. The reaction mixture wasevaporated and quenched with saturated sodium bicarbonate solution,extracted with ethyl acetate, washed with water followed by brine. Theorganic part was dried over sodium sulphate and concentrated to affordthe desired compound6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one(210 mg, 55.41% yield, 90% Purity) as brown solid. LCMS (ES+)=377.0[M+H].

Step-5: Synthesis of3-[6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-1H-benzo[cd]indol-2-one(200 mg, 531.32 umol) in THF (15 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (212.51 mg, 5.31 mmol, 60%purity) portionwise at 0° C. and stirred for 10 mins maintain at 0° C.After that slowly added 3-bromopiperidine-2,6-dione (510.09 mg, 2.66mmol) then reaction mass stirred allowed to 85° C. for 1 hr. Theprogress of the reaction was monitored by TLC, SM was consumed in TLC.Then the reaction mass quenched with ice water and the reaction mixturewas extracted with ethyl acetate and ethyl acetate part washed withwater, followed by brine. The organic part was dried over sodiumsulphate and concentrated under reduced pressure to give the crude. Thiscrude was purified by Preparative HPLC to afford3-[6-[[3-fluoro-4-(morpholinomethyl)phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(50 mg, 19.13% yield, 99.12% purity) as yellow solid. 1H NMR (400 MHz,DMSO-d6): δ 11.12 (s, 1H), 8.34 (d, J=8.2 Hz, 1H), 8.08 (d, J=6.9 Hz,1H), 7.82 (t, J=7.6 Hz, 1H), 7.43 (d, J=7.3 Hz, 1H), 7.27 (t, J=7.8 Hz,1H), 7.12-7.07 (m, 3H), 5.46-5.42 (m, 1H), 4.39 (s, 2H), 3.52-3.50 (m,4H), 3.42 (s, 2H), 2.99-2.91 (m, 1H), 2.79-2.73 (m, 1H), 2.70-2.63 (m,1H), 2.31 (m, 4H), 2.10-2.07 (m, 1H). LCMS (ES+)=488.2 [M+H]+.

Example 162. Synthesis of4-[4-[[5-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]-2-pyridyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile(Compound 279)

Step-1: Synthesis of methyl 6-(chloromethyl)pyridine-3-carboxylate:Methyl 6-(hydroxymethyl)pyridine-3-carboxylate (1 g, 5.98 mmol) wasadded portionwise to Thionyl chloride (14.23 g, 119.60 mmol, 8.68 mL) inice cold condition and stirred the reaction mixture for 2 hr at 25° C.The reaction mixture was evaporated then quenched with sodiumbicarbonate solution extracted with ethyl acetate. The organic layer waswashed with water followed by brine and dried over sodium sulphate andconcentrated. The crude material was purified by column chromatographyby 20% ethyl acetate in hexane to afford methyl6-(chloromethyl)pyridine-3-carboxylate (600 mg, 52.98% yield, 98%Purity) as yellowish solid. LCMS (ES+)=186.2 [M+H]+.

Step-2: Synthesis of [6-(chloromethyl)-3-pyridyl]methanol: To a stirredsolution of methyl 6-(chloromethyl)pyridine-3-carboxylate (3.5 g, 18.86mmol) in THF (40 mL) was cooled −40° C. and Diisobutylaluminum hydride,25% w/w in hexane (21.45 g, 37.71 mmol, 30.61 mL, 25% purity) was addeddropwise. The reaction mixture was stirred at ambient temperature for 2hr. The reaction mixture was quenched with 20% Sodium potassium tertratesolution and extracted with ethyl acetate. The organic layer was washedwith water followed by brine and dried over sodium sulphate,concentrated to afford [6-(chloromethyl)-3-pyridyl]methanol (1.9 g,57.54% yield, 90% Purity) as deep brown gum. LCMS (ES+)=157.9 [M+H]+.

Step-3: Synthesis of3-fluoro-4-[4-[[5-(hydroxymethyl)-2-pyridyl]methyl]piperazin-1-yl]benzonitrile:To stirred solution of 3-fluoro-4-piperazin-1-yl-benzonitrile (2 g, 8.11mmol, 021) in DMF (20 mL) was added Potassium carbonate, anhydrous, 99%(2.80 g, 20.26 mmol, 1.22 mL) stirred for 10 minutes and then[6-(chloromethyl)-3-pyridyl]methanol (1.53 g, 9.73 mmol) was added andstirred the reaction mixture at 60° C. for 8 hr. TLC reaction mixturewas filtered through a celite bed and diluted with ethyl acetate andwashed with water followed by brine. The reaction mixture was dried overSodium sulphate and concentrated. Purified by silica gel chromatographyby 12-15% Ethyl acetate in hexane to afford3-fluoro-4-[4-[[5-(hydroxymethyl)-2-pyridyl]methyl]piperazin-1-yl]benzonitrile(1.5 g, 55.84% yield, 100% Purity) as a white solid. LCMS (ES+)=327.5[M+H]+.

Step-4: Synthesis of4-[4-[[5-(chloromethyl)-2-pyridyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile:3-fluoro-4-[4-[[5-(hydroxymethyl)-2-pyridyl]methyl]piperazin-1-yl]benzonitrile(1.2 g, 3.68 mmol) was added portionwise to Thionyl chloride (13.12 g,110.31 mmol, 8.00 mL) in ice cold condition and stirred the reactionmixture for 2 hr at 25° C. The reaction mixture was evaporated thenquenched with sodium bicarbonate solution extracted with ethyl acetate.The organic layer was washed with water followed by brine and dried oversodium sulphate and concentrated. The material was titurated withPentane to afford4-[4-[[5-(chloromethyl)-2-pyridyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile(1 g, 74.93% yield, 95% Purity) as yellowish solid. LCMS (ES+)=345.1[M+H]+.

Step-5: Synthesis of3-fluoro-4-[4-[[5-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]-2-pyridyl]methyl]piperazin-1-yl]benzonitrile:To a stirred solution of4-[4-[[5-(chloromethyl)-2-pyridyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile(1 g, 2.90 mmol) intoluene (16 mL) and Ethanol (8 mL) was added6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[cd]indol-2-one6 (1.71 g, 5.80 mmol), tripotassium phosphate (1.54 g, 7.25 mmol). Thereaction mixture was degassed with argon for 15 minutes. Thentris-o-tolylphosphane (176.54 mg, 580.02 umol) andTris(Dibenzylideneacetone)dipalladium (0) (265.57 mg, 290.01 umol) wasadded and again purged for 5 minutes. The reaction mixture was stirredand heated at 100° C. for 14 hr. The reaction mixture was evaporated anddiluted with ethyl acetate and washed with water, followed by brine. Theorganic layer was dried over sodium sulphate and concentrated. The crudematerial was purified by silica gel column chromatography by 15-20%ethyl acetate in hexane to afford3-fluoro-4-[4-[[5-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]-2-pyridyl]methyl]piperazin-1-yl]benzonitrile(400 mg, 25.99% yield, 90% Purity) as yellowish solid. LCMS (ES+)=478.3[M+H]+.

Step-6: Preparation of4-[4-[[5-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]-2-pyridyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile:To a stirred solution of3-fluoro-4-[4-[[5-[(2-oxo-1H-benzo[cd]indol-6-yl)methyl]-2-pyridyl]methyl]piperazin-1-yl]benzonitrile7 (400 mg, 837.64 umol) in THF (20 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (320.96 mg, 8.02 mmol, 60%purity) portionwise at 0° C. and stirred for 10 mins maintain at 0° C.After that slowly added 3-bromopiperidine-2,6-dione (804.18 mg, 4.19mmol) then reaction mass stirred allowed to 85° C. for 1 hr. Theprogress of the reaction was monitored by TLC, SM was consumed in TLC.Then the reaction mass quenched with cool ice water and the reactionmixture was diluted with ethyl acetate and washed with water, organiclayer separated, dried over sodium sulphate and concentrated underreduced pressure to give the crude. This crude was purified byPreparative HPLC to afford4-[4-[[5-[[1-(2,6-dioxo-3-piperidyl)-2-oxo-benzo[cd]indol-6-yl]methyl]-2-pyridyl]methyl]piperazin-1-yl]-3-fluoro-benzonitrile8 (88 mg, 17.49% yield, 97.98% purity) Compound 279 as yellow solid.LCMS (ES+)=589.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H),8.55 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.09 (d, J=7.0 Hz, 1H), 7.32 (t,J=7.7 Hz, 1H), 7.69-7.61 (m, 2H), 7.55 (d, J=8.4 Hz, 1H), 7.44 (d, J=7.4Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.13-7.11 (m, 2H), 5.46-5.42 (m, 1H),4.41 (s, 2H), 3.59 (s, 2H), 3.15 (m, 4H), 2.99-2.90 (m, 1H), 2.81-2.73(m, 1H), 2.70-2.63 (m, 1H), 2.63-2.52 (m, 4H, merged with solvent peak),2.10 (m, 1H).

Example 163. Synthesis of3-[6-[[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 280) and3-[6-[[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 281)

Step-1: Synthesis of6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one:32-[(4-methoxyphenyl)methyl]-23-[[1-(1-methyl-4-piperidyl)pyrazol-4-yl]methyl]-28,32-diazatricyclododeca-2(4),3(20),10(23),21(24),25 (28)-pentaen-27-one;2-methylpropan-2-ol; hydrate(600 mg, 1.07 mmol) in DCM (3 mL) in cooled condition was added TFA(2.44 g, 21.44 mmol, 1.65 mL) drop wise. The reaction mixture wasstirred at 25° C. for 14 hr. The reaction mixture was evaporated andquenched with saturated sodium bicarbonate solution, extracted withethyl acetate, washed with water followed by brine. The organic part wasdried over sodium sulphate and concentrated and we get6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one (390 mg,72.19% yield, 90% purity) as solid. LCMS (ES+)=333.4 [M+H]⁺.

Step-2 & Step 3: Synthesis of6-[[1-[1-(1-cyclobutylethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one,6-[[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]ethyl]-1H-benzo[cd]indol-2-oneand6-[[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one:To the stirred solution of6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(500 mg, 1.36 mmol) in THF (10 mL) was added Triethylamine (274.33 mg,2.71 mmol, 377.87 uL) followed by the addition of 1-cyclobutylethanone(159.64 mg, 1.63 mmol, 177.38 uL), Dibutyltindichloride (494.25 mg, 1.63mmol, 363.42 uL) and Phenylsilane (146.68 mg, 1.36 mmol, 167.06 uL). Thereaction mixture was then stirred at 90° C. for 16 hours. TLC waschecked which showed formation of the desired spot. The reaction mixturewas diluted with ethyl acetate, washed with sodium bicarbonate solution,water and brine solution. The organic fraction was separated. It wasdried over anhydrous sodium sulphate, evaporated under reduced pressureto obtain the crude compound which was purified by flash chromatographyusing 3-5% MeOH-DCM to afford cpd-36-[[1-[1-(1-cyclobutylethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-oneas enantiomeric mixture, which was further purified by chiral Prep HPLCusing C Amylose A (250×30 mm) 5μ, in a mobile phase of 40% CO₂+60% (0.3%Isopropylamine in MeOH, at a flow rate of 25 g/min, ABPR: 100 bar andTemperature: 35° C., to afford 3a6-[[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(105 mg, 18.50% Yield, 99% Purity, ee: 100%) first eluent from thechiral column assigned as peak-1 along with 3b6-[[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(110 mg, 19.38% Yield, 99% Purity, ee: 98.10%) second eluent from thechiral column assigned as Peak-2 LC-MS: (ES+)=415.4 [M+H]⁺.

Step-4 Synthesis of 4a: Synthesis of3-(6-((1-(1-(1-cyclobutylethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione:To a stirred solution of6-[[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(100 mg, 241.23 umol) in THF (10 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (92.43 mg, 2.31 mmol, 60%purity) portion wise at 0° C. and stirred for 10 mins maintain at 0° C.After that slowly added 3-bromopiperidine-2,6-dione (231.59 mg, 1.21mmol) then reaction mass stirred allowed to 85° C. for 1 hr. Theprogress of the reaction was monitored by TLC and LCMS, SM was consumedin TLC. Then the reaction mass quenched with cool ice water and thereaction mixture was diluted with ethyl acetate and washed with water,organic layer separated, dried over sodium sulphate and concentratedunder reduced pressure to give the crude. This crude was purified byPreparative HPLC to afford3-[6-[[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 280 (48 mg, 36.48% yield, 96.38% purity) as yellow solid. LCMS(ES+)=526.2 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.38 (d,J=8.4 Hz, 1H), 8.08 (d, J=6.9 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.56 (s,1H), 7.35 (d, J=7.3 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J=7.1 Hz, 1H),5.45-5.42 (m, 1H), 4.17 (s, 2H), 3.94 (m, 1H), 2.95-2.92 (m, 1H),2.76-2.57 (m, 4H), 2.45 (m, 1H), 2.37-2.32 (m, 2H), 2.19-2.14 (m, 1H),2.09-2.08 (m, 1H), 1.89-1.81 (m, 4H), 1.77-1.67 (m, 5H), 1.61-1.59 (m,1H), 0.79 (d, J=6.4 Hz, 3H).

Step 4: Synthesis of 4b: Synthesis of3-[6-[[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(100.00 mg, 241.23 umol) in THF (10 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (92.43 mg, 2.31 mmol, 60%purity) portion wise at 0° C. and stirred for 10 mins maintain at 0° C.After that slowly added 3-bromopiperidine-2,6-dione (231.59 mg, 1.21mmol) then reaction mass stirred allowed to 85° C. for 1 hr. Theprogress of the reaction was monitored by TLC and LCMS, SM was consumedin TLC. Then the reaction mass quenched with cool ice water and thereaction mixture was diluted with ethyl acetate and washed with water,organic layer separated, dried over sodium sulphate and concentratedunder reduced pressure to give the crude. This crude was purified byPreparative HPLC to afford3-[6-[[1-[1-[1-cyclobutylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 281 (44 mg, 33.45% yield, 96.4% purity) as yellow solid. LCMS(ES+)=526.3 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.38 (d,J=8.2 Hz, 1H), 8.08 (d, J=6.9 Hz, 1H), 7.83 (t, J=7.5 Hz, 1H), 7.56 (s,1H), 7.35 (d, J=7.3 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J=7.2 Hz, 1H),5.44-5.42 (m, 1H), 4.17 (s, 2H), 3.97-3.94 (m, 1H), 2.95-2.92 (m, 1H),2.76-2.63 (m, 5H), 2.37-2.30 (m, 2H), 2.17-2.14 (m, 1H), 2.08-2.06 (m,1H), 1.89-1.81 (m, 4H), 1.77-1.67 (m, 5H), 1.61-1.59 (m, 1H), 0.78 (d,J=6.4 Hz, 3H).

Example 164. Synthesis of3-(6-((1-(1-(1-cyclopropylethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 282) and3-(6-((1-(1-(1-cyclopropylethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione(Compound 283)

Step-1 & Step 2: Synthesis of6-((1-(1-(1-cyclopropylethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-2(1H)-one,6-[[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-oneand6-[[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one:To the stirred solution of6-[[1-(1-chloro-4-piperidyl)pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(750 mg, 2.03 mmol) in THF (12 mL) was added Triethylamine (411.50 mg,4.07 mmol, 566.80 uL) followed by the addition of 1-cyclopropylethanone(205.24 mg, 2.44 mmol, 241.74 uL), Dibutyltindichloride (741.38 mg, 2.44mmol, 545.13 uL) and Phenylsilane (220.02 mg, 2.03 mmol, 250.60 uL). Thereaction mixture was then stirred at 90° C. for 16 hours. TLC waschecked which showed formation of the desired spot. The reaction mixturewas diluted with ethyl acetate, washed with sodium bicarbonate solution,water and brine solution. The organic fraction was separated. It wasdried over anhydrous sodium sulphate, evaporated under reduced pressureto obtain the crude compound which was purified by flash chromatographyusing 3-5% MeOH-DCM to to afford cpd-26-[[1-[1-(1-cyclopropylethyl)-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-oneas enantiomeric mixture, which was further purified by chiral Prep HPLCusing Chiralpak IG (250×20 mm) 5μ with mobile phase of 55% CO₂+45% (0.5%Isopropylamine in Methanol, at a flow rate of 25 g/min, ABPR: 120 barand Temperature: 35° C., to afford 2a6-[[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(90 mg, 10.94% Yield, 99% Purity, ee:97.56%) first eluent from thechiral column assigned as peak-1 along with 2b6-[[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(80 mg, 9.73% Yield, 99% Purity, ee: 100%) second eluent from the chiralcolumn assigned as Peak-2 LC-MS: (ES+)=401.1 [M+H]⁺.

Step-3 part 3a: Synthesis of3-[6-[[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(85 mg, 212.23 umol) in THF (10 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (81.32 mg, 2.03 mmol, 60%purity) portion wise at 0° C. and stirred for 10 mins maintain at 0° C.After that slowly added 3-bromopiperidine-2,6-dione (203.75 mg, 1.06mmol) then reaction mass stirred allowed to 85° C. for 1 hr. Theprogress of the reaction was monitored by TLC and LCMS, SM was consumedin TLC. Then the reaction mass quenched with cool ice water and thereaction mixture was diluted with ethyl acetate and washed with water,organic layer separated, dried over sodium sulphate and concentratedunder reduced pressure to give the crude. This crude was purified byPreparative HPLC to afford3-[6-[[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 282 (50 mg, 44.41% yield, 96.43% purity) as off white solidLCMS (ES+)=512.3 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H),8.38 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H),7.58 (s, 1H), 7.35 (d, J=7.3 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.3 Hz,1H), 5.46-5.41 (m, 1H), 4.18 (s, 2H), 4.02-4.00 (m, 1H), 3.06 (m, 1H),2.99-2.91 (m, 2H), 2.77-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.33 (m, 1H),2.25 (m, 1H), 2.09-1.82 (m, 6H), 1.04 (s, 3H), 0.74 (m, 1H), 0.49 (m,1H), 0.39 (m, 1H), 0.23 (m, 1H), 0.01 (m, 1H).

Step 3 part 3b: Synthesis of3-[6-[[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-1H-benzo[cd]indol-2-one(75.00 mg, 187.26 umol) in THF (10 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (71.75 mg, 1.79 mmol, 60%purity) portion wise at 0° C. and stirred for 10 mins maintain at 0° C.After that slowly added 3-bromopiperidine-2,6-dione (179.78 mg, 936.29umol) then reaction mass stirred allowed to 85° C. for 1 hr. Theprogress of the reaction was monitored by TLC and LCMS, SM was consumedin TLC. Then the reaction mass quenched with cool ice water and thereaction mixture was diluted with ethyl acetate and washed with water,organic layer separated, dried over sodium sulphate and concentratedunder reduced pressure to give the crude. This crude was purified byPreparative HPLC to afford3-[6-[[1-[1-[1-cyclopropylethyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 283 (47 mg, 48.66% yield, 99.19% purity) as off white solid.LCMS (ES+)=512.5 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H),8.38 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H),7.58 (s, 1H), 7.35 (d, J=7.3 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=7.3 Hz,1H), 5.44-5.41 (m, 1H), 4.18 (s, 2H), 3.99 (m, 1H), 3.03 (m, 1H),2.95-2.92 (m, 2H), 2.76-2.73 (m, 1H), 2.67-2.63 (m, 1H), 2.33-2.24 (m,2H), 2.08 (m, 1H), 1.89-1.79 (m, 5H), 1.02 (d, J=6.2 Hz, 3H), 0.72-0.71(m, 1H), 0.48 (m, 1H), 0.37 (m, 1H), 0.22 (m, 1H), −0.02 (m, 1H).

Example 165. Synthesis of3-[6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 284) and3-[6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 285)

Step-1: Synthesis of 1-(1-(4-bromophenyl)ethyl)-4-(2-fluorophenyl)piperazine: To a stirred solution of1-bromo-4-(1-bromoethyl)benzene (5.0 g, 18.94 mmol) in DMF (50 mL) wasadded Sodium carbonate (2.01 g, 18.94 mmol, 793.56 uL) and followed by1-(2-fluorophenyl)piperazine (3.41 g, 18.94 mmol) was added at RT andreaction mixture was stirred at RT for 16 hr. The progress of thereaction was monitored by TLC, after reaction completion reactionmixture was diluted with ethyl acetate and gave water wash and followedby brine wash separate out organic layer dried over anhydrous sodiumsulfate filtered and concentrate under reduced pressure to get the crudecompound and it was purified by column chromatography eluted with 0 to30% ethyl acetate in hexane to get1-[1-(4-bromophenyl)ethyl]-4-(2-fluorophenyl)piperazine (5.0 g, 71.21%yield) as off-white solid. LC-MS (ES+)=362.7 [M+H]+.

Step-2: Synthesis of1-(2-fluorophenyl)-4-(1-(4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)piperazine:To a stirred solution of1-[1-(4-bromophenyl)ethyl]-4-(2-fluorophenyl)piperazine (5.00 g, 13.76mmol) and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(3.50 g, 13.76 mmol) and Potassium acetate (3.38 g, 34.41 mmol, 2.15 mL)in a sealed tube 1,4-Dioxane (10 mL) was degassed for 10 mins, later[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (562.01 mg, 688.20 umol) was added again degassedfor 5 mins, after degassing reaction mixture was stirred at 90° C. for16 hr. The progress of the reaction was monitored by TLC, after reactioncompletion reaction mixture was filtered through celite bed and bed waswashed with ethyl acetate and solvent was mixed and concentrated underreduced pressure to get the crude compound and resultant crude waspurified by column chromatography eluted with 0 to 20% ethyl acetate inHexane to get1-(2-fluorophenyl)-4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]piperazine(4.0 g, 67.28% yield) as off-white solid. LC-MS: (ES+)=410.9 [M+H]+.

Step-3: Synthesis of 6-(4-(1-(4-(2-fluorophenyl) piperazin-1-yl) ethyl)benzyl)-1-(4-methoxybenzyl) benzo[cd]indol-2(1H)-one: In a sealed tube6-(chloromethyl)-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one (1.0 g,2.96mmol),1-(2-fluorophenyl)-4-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]piperazine(1.50 g, 3.66 mmol) and Potassium phosphate (1.57 g, 7.40 mmol) wasadded intoluene (24 mL) and Ethanol (12 mL) and degassed for 10 mins,later Tris(o-tolyl)phosphine (180.20 mg, 592.07 umol) andTris(dibenzylideneacetone)dipalladium(0) (271.08 mg, 296.03 umol) wasadded and again degassed for 10 mins, after degassing sealed tube wasclosed with Teflon cap and stirred at 90° C. for 6 hr. The progress ofthe reaction was monitored by TLC, after reaction completion reactionmixture was filtered through celite bed and washed with ethyl acetate,solvent was mixed and concentrated under reduced pressure to get thecrude compound and it was purified by column chromatography eluted with10 to 50% ethyl acetate in Hexane to get6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(0.600 g, 32.87% yield) as yellow solid. LC-MS: (ES+)=585.71 [M+H]+.

Step-4: Synthesis of 6-(4-(1-(4-(2-fluorophenyl) piperazin-1-yl) ethyl)benzyl) benzo[cd]indol-2(1H)-one,6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1H-benzo[cd]indol-2-oneand6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(0.600 g, 1.02 mmol) in Trifluoroacetic acid (10 mL) was cooled to 0° C.later Triflic acid (768.71 mg, 5.12 mmol, 449.54 uL) was added thenreaction mixture was stirred at RT for 16 hr. The progress of thereaction was monitored by TLC, after reaction completion reactionmixture was concentrated then resultant compound was dissolved in ethylacetate and gave saturated solution of sodium bi carbonate and followedby brine solution, separate out organic layer dried over anhydroussodium sulfate filtered and concentrated under reduced pressure to getthe crude compound and it was purified by column chromatography elutedwith 0 to 60% ethyl acetate to get cpd-7 6-[[4-[1-[4-(2fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1H-benzo[cd]indol-2-oneas enantiomeric mixture. Which was further purified by chiral Prep HPLCa Column name: Chiralpak IG (21×250 mm), 5μ; Mobile Phase: Hexane/DiChloro Methane/EtOH: 70/15/15; Flow rate: 21.0 ml/min, Run time: 20 min,Wave length: 252 nm and Solubility: MeOH to afford 7a6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(0.150 g, 318.97 umol, 31.14% yield, 99% purity) first eluent from thechiral column assigned as peak-1 along with 7b6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(0.150 g, 30.82% yield) second eluent from the chiral column assigned asPeak-2. LC-MS: (ES+)=466.0 [M+H]+.

Step-5: Synthesis of3-[6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(100 mg, 214.80 umol) in THF (10 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (98.76 mg, 2.58 mmol, 60%purity) portionwise at 0° C. and stirred for 10 mins maintain at 0° C.After that slowly added 3-bromopiperidine-2,6-dione (247.46 mg, 1.29mmol) then reaction mass stirred allowed to 85° C. for 2 hr. Theprogress of the reaction was monitored by TLC, SM was consumed in TLC.Then the reaction mass quenched with cool ice water and the reactionmixture was diluted with ethyl acetate and washed with water, organiclayer separated, dried over sodium sulphate and concentrated underreduced pressure to give the crude. This crude was purified byPreparative HPLC to afford3-[6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 284 (45 mg, 36.30% Yield) as yellow solid. LCMS (ES+)=577.3[M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.36 (d, J=8.2 Hz,1H), 8.08 (d, J=6.8 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.41 (d, J=7.3 Hz,1H), 7.26-7.20 (m, 4H), 7.11-7.05 (m, 3H), 6.99-6.97 (m, 2H), 5.46-5.42(m, 1H), 4.38 (s, 2H), 3.39-3.37 (m, 1H), 3.29 (m, 1H), 2.95 (m, 5H),2.79-2.70 (m, 1H), 2.67-2.63 (m, 1H), 2.42-2.41 (m, 3H), 2.11-2.08 (m,1H), 1.26 (t, J=6.5 Hz, 3H).

Step 5: Synthesis of3-[6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(100 mg, 214.80 umol) in THF (10 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (98.76 mg, 2.58 mmol, 60%purity) portionwise at 0° C. and stirred for 10 mins maintain at 0° C.After that slowly added 3-bromopiperidine-2,6-dione (247.46 mg, 1.29mmol) then reaction mass stirred allowed to 85° C. for 2 hr. Theprogress of the reaction was monitored by TLC, SM was consumed in TLC.Then the reaction mass quenched with cool ice water and the reactionmixture was diluted with ethyl acetate and washed with water, organiclayer separated, dried over sodium sulphate and concentrated underreduced pressure to give the crude. This crude was purified byPreparative HPLC to afford3-[6-[[4-[1-[4-(2-fluorophenyl)piperazin-1-yl]ethyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 285 (50 mg, 40.35% Yield) as yellow solid. LCMS (ES+)=577.3[M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.36 (d, J=8.2 Hz,1H), 8.08 (d, J=7.0 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.41 (d, J=7.3 Hz,1H), 7.26-7.20 (m, 4H), 7.11-7.05 (m, 3H), 6.99-6.97 (m, 2H), 5.46-5.42(m, 1H), 4.38 (s, 2H), 3.39-3.36 (m, 1H), 3.29 (m, 1H), 2.94 (m, 5H),2.79-2.70 (m, 1H), 2.67-2.63 (m, 1H), 2.42-2.41 (m, 3H), 2.10-2.07 (m,1H), 1.26 (t, J=6.5 Hz, 3H).

Example 166. Synthesis of3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 286)

Step-1: Synthesis of1-[(4-bromo-2-methyl-phenyl)methyl]-4-(2-fluorophenyl)piperazine: Tostirred solution of 1-(2-fluorophenyl)piperazine (2 g, 11.10 mmol) inDMF (10 mL) was added Potassium carbonate, anhydrous, 99% (3.07 g, 22.20mmol, 1.34 mL) stirred for 10 minutes and then4-bromo-1-(bromomethyl)-2-methyl-benzene (3.52 g, 13.32 mmol) was addedand stirred the reaction mixture at 25° C. for 16 hr. TLC reactionmixture was filtered through a celite bed and diluted with ethyl acetateand washed with water followed by brine. The reaction mixture was driedover Sodium sulphate and concentrated. Purified by silica gelchromatography by 12-15% Ethyl acetate in hexane to afford the1-[(4-bromo-2-methyl-phenyl)methyl]-4-(2-fluorophenyl)piperazine (3.5 g,85.06% yield, 98% purity) as a white solid; LCMS (ES+)=363.4 [M+H]+.

Step-2: Synthesis of1-(2-fluorophenyl)-4-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine:To a stirred solution of1-[(4-bromo-2-methyl-phenyl)methyl]-4-(2-fluorophenyl)piperazine (2 g,5.51 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.68 g, 6.61 mmol) and Potassium Acetate (1.35 g, 13.76 mmol, 860.40uL) in 1,4-Dioxane (25 mL) was purged with Argon for 10 minutes thencyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(449.61 mg, 550.56 umol) was added and heated the reaction mixture for14 hr at 90° C. The reaction mixture was diluted with ethyl acetate andwashed with water followed by brine. The organic layer was dried oversodium sulphate and concentrated. The crude material was purified bysilica gel column chromatography by 15% ethyl acetate in hexane toafford the1-(2-fluorophenyl)-4-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine(1 g, 41.17% yield, 93% purity) as a white solid. LCMS (ES+)=411.6[M+H]+.

Step-3: Synthesis of6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one:To a stirred solution of1-(2-fluorophenyl)-4-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine(500 mg, 1.22 mmol) intoluene (8 mL) and Ethanol (4 mL) was addedanisole;6-(chloromethyl)-1-methyl-benzo[cd]indol-2-one (412.85 mg, 1.22mmol), tripotassium phosphate (646.63 mg, 3.05 mmol). The reactionmixture was degassed with argon for 15 minutes. Thentris-o-tolylphosphane (74.18 mg, 243.71 umol) and Tris(Dibenzylideneacetone)dipalladium (0) (111.58 mg, 121.85 umol) was addedand again purged for 5 minutes. The reaction mixture was stirred andheated at 100° C. for 14 hr. The reaction mixture was evaporated anddiluted with ethyl acetate and washed with water, followed by brine. Theorganic layer was dried over sodium sulphate and concentrated. The crudematerial was purified by silica gel column chromatography by 15-20%ethyl acetate in hexane to afford the6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(350 mg, 41.61% yield, 85% purity) as yellowish solid. LCMS (ES+)=586.3[M+H]+.

Step-4: Synthesis of6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(400 mg, 682.93 umol) in TFA (5 mL) was added Triflic acid (1.02 g, 6.83mmol, 599.37 uL) and stirred the reaction mixture at 25° C. for 16 hr.The reaction mixture was evaporated and quenched with saturated sodiumbicarbonate solution, extracted with ethyl acetate, washed with waterfollowed by brine. The organic part was dried over sodium sulphate andconcentrated and triturated with ether and pentane to afford the6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-1H-benzo[cd]indol-2-one(280 mg, 79.26% yield, 90% purity) as yellow solid. LCMS (ES+)=466[M+H]+.

Step-5: Synthesis of3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-1H-benzo[cd]indol-2-one(280 mg, 601.43 umol) in THF (20 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (276.53 mg, 7.22 mmol, 60%purity) portion wise at 0° C. and stirred for 10 mins maintain at 0° C.After that slowly added 3-bromopiperidine-2,6-dione (692.88 mg, 3.61mmol) then reaction mass stirred allowed to 85° C. for 1 hr. Theprogress of the reaction was monitored by TLC, SM was consumed in TLC.Then the reaction mass quenched with cool ice water and the reactionmixture was diluted with ethyl acetate and washed with water, organiclayer separated, dried over sodium sulphate and concentrated underreduced pressure to give the crude. This crude was purified byPreparative HPLC to afford the3-[6-[[4-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-3-methyl-phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 286 (34 mg 9.76% yield, 99.59% purity) as yellow solid, LCMS(ES⁺):577.3 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.34 (d,J=8.2 Hz, 1H), 8.07 (d, J=6.9 Hz, 1H), 7.81 (t, J=7.6 Hz, 1H), 7.40 (d,J=7.3 Hz, 1H), 7.14-7.04 (m, 6H), 7.00-6.91 (m, 2H), 5.46-5.42 (m, 1H),4.37 (s, 2H), 3.41 (s, 1H), 3.3 (m, 2H, merged with solvent peak),2.94-2.91 (m, 5H), 2.81-2.73 (m, 1H), 2.70-2.63 (m, 1H), 2.54 (m, 2H),2.27 (s, 3H), 1.26 (m, 1H).

Example 167. Synthesis of3-[6-[[1-[1-[1-(dimethylamino)cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 287)

Step: 1: Synthesis of:3-[6-[[1-[1-[1-(dimethylamino)cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of 1-(dimethylamino)cyclobutanecarboxylic acid (20mg, 139.68 umol), HCl salt of3-[2-oxo-6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione(67.04 mg, 139.68 umol, 021) in DMF (2 mL) was added TBTU (179.40 mg,279.36 umol, 169.59 uL, 50% purity) and Diisopropyl ethyl amine (90.26mg, 698.41 umol, 121.65 uL) reaction mixture was stirred at 25° C. for16 hr. LCMS showed the desired mass and the reaction mixture was dilutedwith ethyl acetate and washed with water, organic layer separated, driedover sodium sulphate and concentrated under reduced pressure to give thecrude. This crude was purified by silica gel column chromatography(using 2% MeOH in DCM) to give the3-[6-[[1-[1-[1-(dimethylamino)cyclobutanecarbonyl]-4-piperidyl]pyrazol-4-yl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 287 (15 mg, 18.50% yield, 97.97% purity) as yellow solid. LCMS(ES+)=569.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 8.37 (d,J=8.3 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.59 (s,1H), 7.36 (d, J=7.3 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.3 Hz, 1H),5.46-5.41 (m, 1H), 4.48-4.45 (m, 1H), 4.29-4.25 (m, 1H), 4.18 (s, 2H;merged with another 1H), 2.99-2.90 (m, 3H), 2.77-2.63 (m, 2H), 2.32 (m,1H), 2.24-2.23 (m, 2H), 2.14 (s, 6H), 2.09-2.07 (m, 1H), 1.97-1.93 (m,1H), 1.89-1.87 (m, 1H), 1.76-1.59 (m, 4H), 1.57-1.53 (m, 1H).

Example 168. Synthesis of3-[2-oxo-6-[[1-(1-spiro[3.3]heptan-2-yl-4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 288)

Step: 1: Synthesis of:3-[2-oxo-6-[[1-(1-spiro[3.3]heptan-2-yl-4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione:To the stirred solution of HCl salt of3-[2-oxo-6-[[1-(4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dione(100 mg, 208.35 umol, 021) in THF (8 mL) was added Triethylamine, 99%(42.17 mg, 416.70 umol, 58.08 uL) followed by the addition ofspiro[3.3]heptan-2-one (25.25 mg, 229.19 umol), Dibutyltindichloride(75.97 mg, 250.02 umol, 55.86 uL) and Phenylsilane (22.55 mg, 208.35umol, 25.68 uL). The reaction mixture was then stirred at 90° C. for 16hours. TLC was checked which showed formation of the desired spot. Thereaction mixture was diluted with ethyl acetate, washed with sodiumbicarbonate solution, water and brine solution. The organic fraction wasseparated. It was dried over anhydrous sodium sulphate, evaporated underreduced pressure to obtain the crude compound which was purified byflash chromatography using 3-4% MeOH-DCM to afford3-[2-oxo-6-[[1-(1-spiro[3.3]heptan-2-yl-4-piperidyl)pyrazol-4-yl]methyl]benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 288 (50 mg, 43.03% yield, 96.4% purity) as yellow solid LCMS(ES+)=538.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.34 (d,J=8.2 Hz, 1H), 8.05 (d, J=7.0 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 7.54 (s,1H), 7.32 (d, J=7.4 Hz, 1H), 7.26 (s, 1H), 7.04 (d, J=7.3 Hz, 1H),5.43-5.38 (m, 1H), 4.15 (s, 2H), 3.97-3.95 (m, 1H), 2.96-2.88 (m, 1H),2.75-2.69 (m, 2H), 2.67-2.64 (m, 1H), 2.48 (m, 4H, merged with solventpeak), 2.07-2.02 (m, 2H), 1.95-1.91 (m, 2H), 1.86-1.73 (m, 8H),1.69-1.68 (m, 3H).

Example 169. Synthesis of3-[20-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-26-oxo-30,35-diazatricyclododeca-1,3(18),5(20),17(21),22(30)-pentaen-35-yl]piperidine-2,6-dione(Compound 289)

Step-1: Synthesis of 8-bromo-2-oxido-isoquinolin-2-ium: To a stirredsolution of 8-bromoisoquinoline (100 g, 480.64 mmol) in DCM (1500 mL)was added 3-Chloroperoxybenzoic acid, 50-55%, cont. ca 10%3-chlorobenzoic acid, balance water (161.58 g, 720.96 mmol, 77% purity)portion wise and stirred the reaction mixture at 25° C. for 3 hr. TLCshowed total consumption of starting material and formation of the newpolar spot. The reaction mixture was quenched with 2N NaOH solution topH-10 and extracted with DCM. The organic layer was dried over sodiumsulfate and concentrated to afford 8-bromo-2-oxido-isoquinolin-2-ium(80g, 73.54% Yield) as off-white solid. LCMS (ES+)=223.9 [M+H]+.

Step-2: Synthesis of 8-bromo-2H-isoquinolin-1-one: The8-bromo-2-oxido-isoquinolin-2-ium (80 g, 357.06 mmol) was suspended inacetic anhydride (729.03 g, 7.14 mmol, 675.03 mL) and the resultingmixture was heated at reflux for 3 hr then allowed to cool to room temp.The Ac2O was removed by distillation under reduced pressure to yield asolid residue that was suspended in an aqueous solution of NaOH (2 M,600 mL). The resulting mixture was heated at 100° C. for 1 h thenallowed to cool to RT. The pH of the resulting solution was adjusted topH 6 by addition of an aqueous solution of citric acid and the mixturewas extracted with ethyl acetate. The combined organic layers were driedover sodium sulphate and evaporated under reduced pressure to give thecrude product 8-bromo-2H-isoquinolin-1-one (70g, 52.50% Yield). LCMS(ES+)=224.0 [M+H]+.

Step-3: Synthesis of 8-bromo-1-chloro-isoquinoline: To a stirredsolution of 8-bromo-2H-isoquinolin-1-one (40 g, 178.53 mmol) inphosphorus oxy chloride (273.74 g, 1.79 mol, 165.90 mL) was stirred at80° C. for 3 hr. TLC showed total consumption of starting material. Thereaction mixture was evaporated to dryness, basified by saturated sodiumbicarbonate solution and extracted with ethyl acetate. The organic layerwas dried over sodium sulphate and concentrated. The crude material waspurified by column chromatography by 10-15% ethyl acetate in hexane toafford 8-bromo-1-chloro-isoquinoline (20 g, 45.73% Yield) as off-whitesolid. LCMS (ES+)=242.0 [M+H]+.

Step-4: Synthesis of 8-bromo-N-[(4-methoxyphenyl)methyl]isoquinolin-1-amine: 8-bromo-1-chloro-isoquinoline (22 g, 90.72mmol) was taken in a sealed vessel in DMA (120 mL) and 4-methoxy benzylamine (18.67 g, 136.08 mmol, 17.78 mL) was added and the reactionmixture was heated at 120° C. for 3 hr. LCMS showed the desired mass.The reaction mixture was diluted with ethyl acetate and water. Theorganic layer was dried over sodium sulphate and concentrated. Thereaction mixture was purified by column chromatography by 5% ethylacetate in hexane to afforded 8-bromo-N-[(4-methoxyphenyl)methyl]isoquinolin-1-amine (23g, 62.79%) as brown sticky gum. LCMS(ES+)=344.7 [M+H]+.

Step-5: Synthesis of 19-[(4-methoxyphenyl)methyl]-18,19-diazatricyclododeca-1(3),2(12),8,14,16(18)-pentaen-17-one:8-bromo-N-[(4-methoxyphenyl) methyl]isoquinolin-1-amine (20 g, 58.27mmol) was taken in MeOH (500 mL), triethyl amine (23.59 g, 233.09 mmol,32.49 mL) was added and Argon gas was purged for 10 minutes. Then DPPP(4.81 g, 11.65 mmol) and Palladium (II) acetate (1.31 g, 5.83 mmol) wasadded and the reaction mixture was subjected to carbonization inParr-autoclave at 100° C. under 70Psi pressure in the atmosphere ofCarbon monoxide. The reaction mixture was filtered through a celite bedand concentrated. The crude material was worked up with ethyl acetateand water followed by brine. The organic layer was dried over sodiumsulphate and concentrated. The crude material was purified by columnchromatography by 60% ethyl acetate in hexane to afford19-[(4-methoxyphenyl)methyl]-18,19-diazatricyclododeca-1(3),2(12),8,14,16(18)-pentaen-17-one(9.5g, 53.16% Yield) as off white solid. LCMS (ES+)=291.1 [M+H]+.

Step-6: Synthesis of 14-bromo-19-[(4-methoxyphenyl)methyl]-18,19-diazatricyclododeca-1(3),2(12),8(14),13(15),16(18)-pentaen-17-one:To the stirred suspension of19-[(4-methoxyphenyl)methyl]-18,19-diazatricyclododeca-1(3),2(12),8,14,16(18)-pentaen-17-one(7 g, 24.11 mmol) in Acetonitrile (150 mL) was added N-Bromosuccinimide(4.51 g, 25.32 mmol, 2.15 mL) at cold condition drop wise and thereaction was continued at 25° C. for 14 hr hours. LCMS showed thedesired mass and TLC showed new spots. The reaction mixture wasevaporated and quenched with Na2S2O3 solution extracted with ethylacetate. The organic layer was washed with water followed by brine anddried over sodium sulphate and concentrated. The crude material waspurified by column chromatography to afford14-bromo-19-[(4-methoxyphenyl)methyl]-18,19-diazatricyclododeca-1(3),2(12),8(14),13(15),16(18)-pentaen-17-one(5 g, 53.92% Yield) as yellow solid; LCMS (ES+) 369.1 [M+H]+.

Step-7: Synthesis of 21-[(4-methoxyphenyl)methyl]-16-vinyl-20,21-diazatricyclododeca-2(4),3(14),9(16),15(17),18(20)-pentaen-19-one:To a stirred solution of14-bromo-19-[(4-methoxyphenyl)methyl]-18,19-diazatricyclododeca-1(3),2(12),8(14),13(15),16(18)-pentaen-17-one(5 g, 13.54 mmol) intoluene (100 mL) was added Tributyl vinyl tin (6.44g, 20.31 mmol, 5.91 mL). It was degassed with argon for 10 minutes.Tri-tert-butylphosphine (2.5 M, 1.08 mL) and pd2(dba)3 (1.24 g, 1.35mmol) was added to the reaction mixture and was further degassed withargon for 10 minutes. It was stirred at 70° C. for 16 hr. The reactionmixture was then allowed to come to RT, filtered and was extracted withethyl acetate. The organic phase was washed with brine, and finallydried over anhyd. Na₂SO₄. The solvent was evaporated and the residue waspurified by column chromatography on silica gel to afford21-[(4-methoxyphenyl) methyl]-16-vinyl-20,21-diazatricyclododeca-2(4),3(14),9(16),15 (17),18(20)-pentaen-19-one (1.4 g, 31.04% Yield) as yellowsolid. LCMS (ES+)=317.2 [M+H]+.

Step-8: Synthesis of 20-[(4-methoxyphenyl)methyl]-18-oxo-19,20-diazatricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaene-15-carbaldehyde:To a stirred solution of21-[(4-methoxyphenyl)methyl]-16-vinyl-20,21-diazatricyclododeca-2(4),3(14),9(16),15(17),18(20)-pentaen-19-one (2 g, 6.32 mmol) in EtOAc (30mL) and Water (15 mL) were added sodium meta periodate (3.38 g, 15.81mmol) and OsO4 (0.16 M, 790.26 uL) and stirred at RT for 4 h. Aftercompletion of SM, reaction mixture was extracted with EtOAc. The organicphase was washed with brine, and finally dried over anhyd. Na₂SO₄. Thesolvent was evaporated to afford 20-[(4-methoxyphenyl)methyl]-18-oxo-19,20-diazatricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaene-15-carb aldehyde (1.5 g, 70.81% Yield) as awhite solid. LCMS (ES+)=319.0 [M+H]+. Step-9: Synthesis of15-(hydroxymethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diazatricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaen-18-one:To a stirred solution of20-[(4-methoxyphenyl)methyl]-18-oxo-19,20-diazatricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaene-15-carbaldehyde(1.5 g, 4.71 mmol) in MeOH (50 mL) was cooled to zero degree then SodiumBorohydride (267.39 mg, 7.07 mmol, 249.90 uL) was added and stirred at25° C. for 4 hr. The reaction mixture was evaporated then diluted withethyl acetate and washed with water followed by brine. The organic layerwas dried over sodium sulphate and concentrated to afford15-(hydroxymethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diazatricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaen-18-one(1.2 g, 67.57% Yield) as brown solid; LC-MS: (ES+) 321.1 [M+H]+.

Step-10: Synthesis of 15-(chloromethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diazatricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaen-18-one:Thionyl Chloride (4.46 g, 37.46 mmol, 2.72 mL) in cold condition wasadded15-(hydroxymethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diazatricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaen-18-one(1.2 g, 3.75 mmol) and stirred at 25° C. for 3 hr. The reaction mixturewas evaporated then quenched with sodium bicarbonate solution extractedwith ethyl acetate. The organic layer was washed with water followed bybrine and dried over sodium sulphate and concentrated. The crudematerial was titurated with pantane and ether to afford15-(chloromethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diazatricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaen-18-one(900 mg, 53.19% Yield) as brown solid. LCMS (ES+)=339 [M+H]+.

Step-11: Synthesis of32-[(4-methoxyphenyl)methyl]-23-[[1-(1-methyl-4-piperidyl)pyrazol-4-yl]methyl]-28,32-diazatricyclododeca-2(4),3(20),10(23),21(24),25(28)-pentaen-27-one;2-methylpropan-2-ol;hydrate: To a stirred solution of15-(chloromethyl)-20-[(4-methoxyphenyl)methyl]-19,20-diazatricyclododeca-1(3),2(13),8(15),14(16),17(19)-pentaen-18-one(900 mg, 2.66 mmol) intoluene (16 mL) and Ethanol (8 mL) was added1-hydroxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine;methane; 2-methylpropan-2-ol (1.01 g, 2.66 mmol), tripotassium phosphate(1.41 g, 6.64 mmol). The reaction mixture was degassed with argon for 15minutes. Then tris-o-tolylphosphane (161.71 mg, 531.31 umol) andTris(Dibenzylideneacetone)dipalladium (0) (243.26 mg, 265.65 umol) wasadded and again purged for 10 minutes. The reaction mixture was stirredand heated at 100° C. for 14 hr. The reaction mixture was evaporated anddiluted with ethyl acetate and washed with water, followed by brine. Theorganic layer was dried over sodium sulphate and concentrated. LCMSshowed the desired mass and the reaction mixture was purified by columnchromatography by 3-4% MeOH in DCM to afford32-[(4-methoxyphenyl)methyl]-23-[[1-(1-methyl-4-piperidyl)pyrazol-4-yl]methyl]-28,32-diazatricyclododeca-2(4),3(20), 10(23),21(24),25(28)-pentaen-27-one;2-methylpropan-2-ol; hydrate(900 mg, 42.52% Yield) as yellowish solid. LCMS (ES+)=554.5 [M+H]+.

Step-12: Synthesis of31-[(4-methoxyphenyl)methyl]-22-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-27,31-diazatricyclododeca-1(3),2(19),9(22),20(23),24(27)-pentaen-26-one:32-[(4-methoxyphenyl)methyl]-23-[[1-(1-methyl-4-piperidyl)pyrazol-4-yl]methyl]-28,32-diazatricyclododeca-2(4),3(20), 10(23),21(24),25 (28)-pentaen-27-one;2-methylpropan-2-ol; hydrate(600 mg, 1.07 mmol) in DCM (3 mL) in cooled condition was added TFA(2.44 g, 21.44 mmol, 1.65 mL) dropwise. The reaction mixture was stirredat 25° C. for 14 hr. The reaction mixture was evaporated and quenchedwith saturated sodium bicarbonate solution, extracted with ethylacetate, washed with water followed by brine. The organic part was driedover sodium sulphate and concentrated to afford31-[(4-methoxyphenyl)methyl]-22-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-27,31-diazatricyclododeca1(3),2(19),9(22),20(23),24(27)-pentaen-26-one (390 mg, 72.19% Yield) as yellowish solid.

Step-13: Synthesis of 37-[(4-methoxyphenyl)methyl]-26-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-33,37-diazatricyclododeca-2(4),3(23),10(26),24(27),28(33)-pentaen-30-one:To a stirred solution of 1-methylcyclobutanecarboxylic acid (47.82 mg,418.93 umol) and31-[(4-methoxyphenyl)methyl]-22-[[1-(4-piperidyl)pyrazol-4-yl]methyl]-27,31-diazatricyclododeca1(3),2(19),9(22),20(23),24(27)-pentaen-26-one (190 mg, 418.93 umol) in DMF (3 mL) wasadded DIPEA (270.71 mg, 2.09 mmol, 364.84 uL) and HATU (238.94 mg,628.40 umol) reaction mixture was stirred at 25° C. for 16 hr. Accordingto LCMS there was shown the desired mass and the reaction mixture wasdiluted with ethyl acetate and washed with water, organic layerseparated, dried over sodium sulphate and concentrated under reducedpressure to give the crude. This crude was purified by columnchromatography (using 3% MeOH in DCM) to of 37-[(4-methoxyphenyl)methyl]-26-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-33,37-diazatricyclododeca-2(4),3(23),10(26),24(27),28(33)-pentaen-30-one(90 mg, 38.69% Yield) as brown solid. LCMS (ES+)=550.4 [M+H]+.

Step-14: Synthesis of18-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-25,27-diazatricyclododeca-1,3(16),5(18),15(19),20(25)-pentaen-22-one:37-[(4-methoxyphenyl)methyl]-26-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-33,37-diazatricyclododeca-2(4),3(23),10(26),24(27),28(33)-pentaen-30-one (90 mg, 163.74 umol) in TFA (3mL) in cooled condition was added Triflic acid (368.61 mg, 2.46 mmol,215.56 uL) dropwise. The reaction mixture was stirred at 25° C. for 16hr. The reaction mixture was evaporated and quenched with saturatedsodium bicarbonate solution, extracted with ethyl acetate, washed withwater followed by brine. The organic part was dried over sodium sulphateand concentrated to afford18-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-25,27-diazatricyclododeca-1,3(16),5(18),15(19),20(25)-pentaen-22-one(60 mg, 71.66% Yield) as brown solid. LCMS (ES+)=430.3[M+H].

Step-15: Synthesis of3-[20-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-26-oxo-30,35-diazatricyclododeca-1,3(18),5(20),17(21),22(30)-pentaen-35-yl]piperidine-2,6-dione:To a stirred solution of18-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-25,27-diazatricyclododeca-1,3(16), 5(18),15(19),20(25)-pentaen-22-one (45.00 mg, 104.77 umol) and3-bromopiperidine-2,6-dione (60.35 mg, 314.31 umol) in THF (3 mL) inArgon atmosphere was added Lithium bis(trimethylsilyl)amide (1 M, 628.62uL) dropwise in ice cold condition and heated the reaction mixture at65° C. for 4 hr. LCMS showed the desired compound with unreactedstarting material. The reaction mixture was quenched with ice andextracted with ethyl acetate, organic layer was washed with brine anddried over sodium sulphate and concentrated. The reaction mixture waspurified by prep HPLC to afford3[20-[[1-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]pyrazol-4-yl]methyl]-26-oxo-30,35-diazatricyclododeca-1,3(18), 5(20),17(21),22(30)-pentaen-35-yl]piperidine-2,6-dione Compound289 (3 mg, 5.21% Yield) as off white solid. LCMS (ES+)=541.2 [M+H]+. 1HNMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 8.14(d, J=8.1 Hz, 1H), 8.09 (s, 1H), 8.00 (t, J=7.6 Hz, 1H), 7.65 (s, 1H),7.35 (s, 1H), 5.41-5.37 (m, 1H), 4.38 (m, 1H), 4.32-4.27 (m, 1H), 4.11(s, 2H), 3.56 (m, 1H), 3.31-2.81 (m, 3H), 2.67-2.63 (m, 2H), 2.41-2.36(m, 2H), 2.13-2.11 (m, 1H), 1.99-1.85 (m, 3H), 1.79-1.75 (m, 3H), 1.67(m, 1H), 1.62-1.59 (m, 1H), 1.34 (s, 3H).

Example 170. Synthesis of3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione(Compound 290)

Step-1: Synthesis of6-[(3-bromophenyl)methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one:To the solution of (3-bromophenyl)boronic acid (2.67 g, 13.28 mmol)intoluene (50 mL) andanisole;6-(chloromethyl)-1-methyl-benzo[cd]indol-2-one (4.5 g, 13.28mmol) and Potassium phosphate tribasic anhydrous (7.05 g, 33.20 mmol)were added the mixture was purged with argon gas for 15 min then addedTetrakis(triphenylphosphine)palladium(0), 99.8% (metals basis), Pd 9%min (1.53 g, 1.33 mmol) was added again argon gas was purged for 5 minand the mixture was stirred at 90° C. for 16 hr in a sealed tube.Completion of reaction confirmed by TLC, after completion of reaction itwas filtered through celite and diluted with ethyl acetate and washedwith water and brine solution. The solvent was evaporated and theresidue was purified by column chromatography on silica gel by 2% ofethyl acetate in pet ether to get the6-[(3-bromophenyl)methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(1.1 g, 9.92% yield, 55% purity) as yellow solid. LCMS (ES+)=460.6[M+H]+.

Step-2: Synthesis of tert-butyl4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate:To the solution of6-[(3-bromophenyl)methyl]-1-[(4-methoxyphenyl)methyl]benzo[cd]indol-2-one(1 g, 2.18 mmol) in Dioxane (20 mL) Dioxane (20 mL) and Water (4 mL) wasadded tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(708.35 mg, 2.29 mmol) and Sodium carbonate (578.11 mg, 5.45 mmol,228.50 uL) were added. The mixture was purged with argon gas for 15 minthen added XPhos Pd G3 (92.34 mg, 109.09 umol) again argon gas waspurged for 5 min and the mixture was stirred at 90° C. for 16 hr in asealed tube. completion of reaction confirmed by TLC, After completionof reaction it was filtered through celite and diluted with ethylacetate and washed with water and saturated sodium carbonate and brinesolution. The solvent was evaporated and the get crude compound. Andpurified by column chromatography on silica gel by 20% of ethyl acetatein hexane to get the tert-butyl4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate(600 mg, yield, 29.43% Yield, 60% purity) as yellow solid. LCMS(ES+)=561 [M+H]+.

Step-3: Synthesis of tert-butyl4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate:To a stirred solution of tert-butyl4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate(750 mg, 1.34 mmol) in Methanol (50 mL) was purged with Argon for 15minutes then Palladium-carbon (10% moist) (200 mg, 1.34 mmol) was addedagain the reaction mixture was purged with Argon. The reaction mixturewas then hydrogenated at Balloon pressure for 16 hr. LCMS showed thedesired mass then the reaction mixture was filtered through a celitebed. The filtrate was then evaporated and purified by prep-HPLC toafford the tert-butyl4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate(130 mg, 17.01% yield, 98.5% purity). LCMS (ES+)=564 [M+H]+.

Step-4: Synthesis of6-[[3-(4-piperidyl)phenyl]methyl]-1H-benzo[cd]indol-2-one: Tert-butyl4-[3-[[1-[(4-methoxyphenyl)methyl]-2-oxo-benzo[cd]indol-6-yl]methyl]phenyl]piperidine-1-carboxylate(210 mg, 373.20 umol) in TFA (3 mL) in cooled condition was addedTriflic acid (280.05 mg, 1.87 mmol, 163.77 uL) drop wise. The reactionmixture was stirred at 25° C. for 16 hr. The reaction mixture wasevaporated and quenched with saturated sodium bicarbonate solution,extracted with ethyl acetate, washed with water followed by brine. Theorganic part was dried over sodium sulphate and concentrated to afford6-[[3-(4-piperidyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (130 mg,86.47% yield, 85% purity). LCMS (ES+)=343 [M+H]+.

Step-5: Synthesis of6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-1H-benzo[cd]indol-2-one:To a stirred solution of6-[[3-(4-piperidyl)phenyl]methyl]-1H-benzo[cd]indol-2-one (130 mg,379.64 umol) and 1-methylcyclobutanecarboxylic acid (43.33 mg, 379.64umol) in DMF (3 mL) was added DIPEA (245.32 mg, 1.90 mmol, 330.62 uL)and HATU (216.52 mg, 569.45 umol) reaction mixture was stirred at 25° C.for 16 hr. According to LCMS there was shown the desired mass and thereaction mixture was diluted with ethyl acetate and washed with water,organic layer separated, dried over sodium sulphate and concentratedunder reduced pressure to give the crude. This crude was purified bycolumn chromatography (using 60% Ethyl acetate in Hexane) to give thetitle compound6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(100 mg, 58.86% yield, 98% purity) as a white solid. LCMS(ES+)=439.0[M+H]+.

Step-6: Synthesis of3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dione:To a stirred solution of6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-1H-benzo[cd]indol-2-one(100 mg, 228.02 umol) in THF (5 mL) was added Sodium hydride (in oildispersion) 60% dispersion in mineral oil (87.37 mg, 2.28 mmol, 60%purity) portion wise at 0° C. and stirred for 10 mins maintain at 0° C.After that slowly added 3-bromopiperidine-2,6-dione (218.91 mg, 1.14mmol) then reaction mass stirred allowed to 75° C. for 20 mins. Theprogress of the reaction was monitored by TLC, SM was consumed in TLC.Then the reaction mass quenched with cool ice water and the reactionmixture was diluted with ethyl acetate and washed with water, organiclayer separated, dried over sodium sulphate and concentrated underreduced pressure to give the crude. This crude was purified byPreparative HPLC afford3-[6-[[3-[1-(1-methylcyclobutanecarbonyl)-4-piperidyl]phenyl]methyl]-2-oxo-benzo[cd]indol-1-yl]piperidine-2,6-dioneCompound 290 (11 mg, 8.65% yield, 98.61% purity), LCMS (ES+)=550.5[M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.36 (d, J=7.8 Hz,1H), 8.07 (d, J=6.6 Hz, 1H), 7.81 (t, J=7.4 Hz, 1H), 7.40 (d, J=7.2 Hz,1H), 7.25 (s, 1H), 7.18-7.16 (m, 1H), 7.11-7.04 (m, 3H), 5.45-5.43 (m,1H), 4.47 (m, 1H), 4.37 (s, 2H), 3.60 (m, 1H), 2.99-2.92 (m, 2H),2.79-2.63 (m, 3H), 2.43 (m, 2H), 2.07 (m, 2H), 1.93-1.88 (m, 1H),1.78-1.72 (m, 4H), 1.63-1.60 (m, 1H), 1.46 (m, 2H), 1.35 (s, 3H).

Example 171. Cell Viability Assay for Table 1 Materials

RPMI 1640 medium, fetal bovine serum (FBS) and 2-mercaptoethanol werepurchased from Gibco (Grand Island, N.Y., USA). CellTiter-Glo® 2.0 Assaywas purchased from Promega (Madison, Wis., USA). NCIH929.1 cell line waspurchased from ATCC (Manassas, Va., USA). Cell culture flasks and384-well microplates were acquired from VWR (Radnor, Pa., USA).

Cell Viability Analysis

NCIH929.1 cell viability was determined based on quantification of ATPusing CellTiter-Glo® 2.0 luminescent Assay kit, which signals thepresence of metabolically-active cells. Briefly, the test compound wasadded to 384-well plates at a top concentration of 1 μM with 10 points,half log titration in duplicates. NCIH929.1 cells were seeded into the384-well plates in RPMI medium containing 10% FBS and 0.05 mM2-mercaptoethanol at a cell density of 750 cells per well. Cells treatedin the absence of the test compound were the negative control and cellstreated in the absence of CellTiter-Glo® 2.0 were the positive control.At the same day of compound treatment, CellTiter-Glo® 2.0 was added to aplate with cells treated in the absence of the test compound toestablish Cytostatic control value (Gm). Cells treated with the testcompound were incubated at 37° C. with 5% CO₂ for 96 hr. CellTiter-Gloreagent was then added to the cells and luminescence was acquired onEnVision™ Multilabel Reader (PerkinElmer, Santa Clara, Calif., USA).

Results

Using the above assay IC₅₀ data was determined for representativecompounds in Table 1 below.

Example 172. Cell Viability Assay for Table 2 Materials

RPMI 1640 medium, fetal bovine serum (FBS) and 2-mercaptoethanol werepurchased from Gibco (Grand Island, N.Y., USA). CellTiter-Glo® 2.0 Assaywas purchased from Promega (Madison, Wis., USA). NCIH929.1 cell line waspurchased from ATCC (Manassas, Va., USA). Cell culture flasks and384-well microplates were acquired from VWR (Radnor, Pa., USA).

Cell Viability Analysis

NCIH929.1 cell viability was determined based on quantification of ATPusing CellTiter-Glo® 2.0 luminescent Assay kit, which signals thepresence of metabolically-active cells. Briefly, test compound was addedto 384-well plates at a top concentration of 1 μM with 14 points, halflog titration in duplicates. NCIH929.1 were seeded into the 384-wellplates in RPMI medium containing 10% FBS and 0.05 mM 2-mercaptoethanolat a cell density of 750 cells per well. Cells treated in the absence ofthe test compound were the negative control, normalized to 100%viability, and cells treated in the absence of CellTiter-Glo® 2.0 werethe positive control, normalized to 0% viability. Cells were incubatedat 37° C. with 5% CO2 for 96 hr. CellTiter-Glo reagent was then added tothe cells and Luminescence was acquired on EnVision™ Multilabel Reader(PerkinElmer, Santa Clara, Calif., USA).

Results

Using the above assay IC₅₀ data was determined for representativecompounds in Table 2 below.

Example 173 Representative Compounds

Where chirality is depicted in the tables below the designation showsthe relative chirality of that stereocenter and not an absolutedesignation. Where a chiral center is not specified then there may be amixture of chiralities at that chiral center for example,

TABLE 1 Compound No. Structure GI₅₀ 2

++++ 3

++++ 4

++++ 18

++++ In the above table: ++++ is < 1 nM; +++ is < 100 nM; ++ is < 999nM, and + > 999 nM.

TABLE 2 IC₅₀ # Structure (nM)  36

3-(2-oxo-6-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  37

++++3-(6-((1-(1-(2-oxabicyclo[2.1.1]hexane-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 38

++++1-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-l,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)cyclopropane-1-carbonitrile  39

++++1-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)cyclobutane-1-carbonitrile  40

++++3-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,2-dimethyl-3-oxopropanenitrile  41

++++3-(6-((1-(1-(4-methyltetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 42

++++ 3-(6-((1-(1-isonicotinoylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  43

++++ 3-(6-((1-(1-nicotinoylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  44

++++ 3-(2-oxo-6-((1-(1-pivaloylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  45

++++3-(6-((1-(1-(2,6-dimethylbenzoyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  46

++++ 3-(2-oxo-6-((1-(1-picolinoylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  47

++++ 3-(6-((1-(1-benzoylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  48

++++3-(6-((1-(1-(2-oxabicyclo[2.1.1]hexane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 49

++++3-(6-((1-(1-(1-methyl-2-oxabicyclo[3.1.1]heptane-5-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 50

++++3-(6-((1-(1-(bicyclo[3.1.1]heptane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  51

++++3-(2-oxo-6-((1-(1-(1-(trifluoromethyl)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 52

++++3-(2-oxo-6-((1-(1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 53

++++3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  54

++++3-(6-((1-(1-(cubane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  55

++++3-(6-((1-(1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  56

++++3-(6-((1-(1-((1-methoxycyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  57

++++3-(2-oxo-6-((1-(1-((1-(trifluoromethyl)cyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  58

++++ 3-(6-((1-(1-(2-methoxy-2-methylpropyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  59

++++3-(6-((1-(1-((1-fluorocyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  60

++++1-((4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclobutane-1-carbonitrile 61

++++3-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,2-dimethylpropanenitrile 62

++++3-(2-oxo-6-((1-(1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  63

++++ 3-(6-((1-(1-neopentylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  64

++++3-(6-((1-(1-((1-methylcyclopropyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  65

++++3-(6-((1-(1-((1-fluorocyclopropyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  66

++++3-(6-((1-(1-((1-methoxycyclopropyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  67

++++3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  68

++++3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  69

+++ 3-(6-((1-(4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  70

++++3-(6-((1-(l-(cubane-1-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  71

++++3-(6-((1-(1-(2-oxabicyclo[2.1.1]hexane-4-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 72

++++1-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carbonyl)cyclohexane-1-carbonitrile  73

+++3-(6-((l-(4-methyl-1-(quinuclidine-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  74

+++3-(6-((1-(1-(1-azabicydo[2.2.1]heptane-4-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 75

++++3-(6-((1-(1-acetyl-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  76

++++3-(6-((1-(1-(1-(difluoromethyl)cyclopropane-1-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 77

++++3-(6-((1-(4-methyl-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 78

++++3-(6-((1-(4-methyl-1-(1-(trifluoromethyl)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 79

++++1-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carbonyl)cyclopropane-1-carbonitrile  80

++++3-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-4-methylpiperidin-1-yl)-2,2-dimethyl-3-oxopropanenitrile  81

++++3-(6-((1-(4-methyl-1-(4-methyltetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 82

++++3-(6-((1-(4-methyl-1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 83

++++3-(6-((1-(4-methyl-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 84

++++3-(6-((1-(1-(2-methoxy-2-methylpropanoyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 85

++++3-(6-((1-(1-(3-methoxy-2,2-dimethylpropanoyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 86

++++1-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carbonyl)cyclobutane-1-carbonitrile  87

3-(6-((1-(1-(cyclopropanecarbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  88

++++ 3-(6-((1-(4-methyl-1-(1-methyl-2-oxabicyclo[3.1.1]heptane-5-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  89

++++3-(6-((1-(1-(bicyclo[3.1.1]heptane-1-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 90

++++3-(6-((1-(1-(2-oxabicyclo[2.1.1]hexane-1-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 91

++++3-(6-((1-(1-(bicyclo[1.1.1]pentane-1-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidinc-2,6-dione 92

++++3-(6-((1-(4-methyl-1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 93

++++3-(6-(1-(4-methyl-1-pivaloylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione  94

++++3-(6-((1-(4-methyl-1-(3-methyloxetane-3-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 95

++++3-(6-((1-(1-(3-fluoro-2,2-dimethylpropanoyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 96

++++3-(6-((1-(1-(2-fluoro-2-methylpropanoyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 97

++++3-(6-((1-(1-(2-chloro-2-methylpropanoyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 98

++++3-(6-((1-(1-(3-hydroxy-2,2-dimethylpropanoyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 99

++++3-(6-((1-(4-methyl-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione100

++++3-(6-((1-(4-methyl-1-((1-methylcyclopropyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione101

++++3-(6-((1-(1-((1-methoxycyclopropyl)methyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione102

++++1-((4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-4-methylpiperidin-1-yl)methyl)cyclopropane-1-carbonitrile103

++++3-(6-((1-(1-((1-methoxycyclobutyl)methyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione104

++++3-(6-((1-(4-methyl-1-neopentylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 105

++++3-(6-((1-(4-methyl-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione106

++++3-(6-((1-(1-((1-fluorocyclopropyl)methyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione107

++++ tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazine-1-carboxylate 108

++++3-(6-(4-((4-acetylpiperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 109

++++ 3-(2-oxo-6-(4-((4-((2,2,2-trifIuoroethyl)sulfonyl)piperazin-1-yl)methyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 110

++++3-(6-(4-((4-(1-methylcyclobutane-1-carbonyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 111

++++3-(6-(4-((4-benzoylpiperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 112

++++ 3-(6-(4-((4-(cyclopropanecarbonyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 113

++++ 3-(6-(4-((4-(cyclopropylmethyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 114

++++3-(6-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 115

++++ 3-(6-(4-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 116

++++ 3-(6-(4-((4-mcthyl-3-oxopiperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidme-2,6-dione 117

++++ 3-(6-(4-(isoindolin-2-ylmethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 118

++++3-(6-(4-((2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 119

++++ 3-(6-(4-((2-(4-fluorophenyl)morpholino)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 120

++++ 3-(6-(4-((3-(4-fluorophenoxy)azetidin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 121

++++3-(2-oxo-6-(4-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione122

++++3-(6-(4-((1,4-dioxidothiomorpholino)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 123

++++3-(6-(4-((1,4-oxazepan-4-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 124

+ methyl 1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carboxylate 125

++++3-(6-((4-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione126

++++3-(6-((1-(1-(3-fluoropyridin-2-yl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 127

++++3-(6-((4-(4-methyl-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 128

++++4-(4-((1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile129

++++4-(4-((1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile130

++++4-(4-((1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile131

++++4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)-4,7-diazaspiro[2.5]octan-7-yl)-3-fluorobenzonitrile132

++++ N-(tert-butyl)-4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-lH-pyrazol-l-yl)-N-methylpiperidine-1-carboxamide133

++++3-(6-((3-chloro-1-(4-methyl-1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione134

++++ 3-(6-(4-(4-(2-fluorophenyl)piperazine-1-carbonyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 135

++++3-(6-(4-((7-(2-fluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 136

+ 3-(2-oxo-6-(prop-2-yn-1-ylamino)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 137

+++ 3-(2-oxo-6-(prop-2-yn-1-yloxy)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 138

3-(6-bromo-2-oxobenzo[cd]indol-1(2H)- yl)piperidine-2,6-dione 139

+++ 3-(2-oxobenzo[cd]indol-1(2H)- yl)piperidine-2,6-dione 140

++++ tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate141

++++ tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate142

++++ tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate143

++ tert-butyl 4-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate144

++ 3-(6-amino-2-oxobenzo[cd]indol-1(2H)- yl)piperidine-2,6-dione 145

+ 1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonitrile 146

++++ 3-(6-(4-((3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl)benzyl)-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 147

++++ tert-butyl 4-(4-(1-(2-oxo-1,2-dihydrobcnzo[cd]indol-6-yl)ethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 148

++++3-(6-(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)ethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 149

++++3-(6-(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)ethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 150

++++3-(6-(4-((1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 151

++++4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperidin-1-yl)-3-fluorobenzonitrile 152

++++3-(6-(4-((1-benzylpiperidin-4-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 153

++++(3S)-3-(6-(amino(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione154

++++ tert-butyl 4-(4-(amino(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate155

++++ 3-(6-(4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzyl)-2-oxobenzo[cd]indol-(2H)-yl)piperidine-2,6-dione 156

++++ 3-(6-(4-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 157

++++ 3-(6-(4-((4-(4-fluorobenzyl)piperidin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 158

++++3-(6-(4-((4-(tert-butyl)piperidin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 159

++++ 3-(2-oxo-6-(4-((4-((2,2,2-trifluoroethyl)sulfonyl)piperazin-1-yl)methyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 160

++++ 3-(2-oxo-6-(4-((4-((2,2,2-trifluoroethyl)sulfonyl)piperazin-1-yl)methyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 161

++++ 3-(2-oxo-6-(4-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)benzyl)benzo[cd]indol-12H)-yl)piperidine-2,6-dione 162

++++3-(6-((1-cyclohexyl-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 163

++++3-(6-(1-(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl-1H-pyrazol-4-yl)cyclopropyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 164

+++3-(6-(1-(1-(1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)cyclopropyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 165

++++4-(4-((4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)phenyl)(methyl)amino)piperidin-1-yl)-3-fluorobenzonitrile 166

++++4-(4-((4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)phenyl)amino)piperidin-1-yl)-3-fluorobenzonitrile 167

++++3-(6-(4-(4-(1-methylcyclobutane-1-carbonyl)piperazin-1-yl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 168

++++ 3-(6-(4-(4-((1-methylcyclobutyl)methyl)piperazin-1-yl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 169

++++3-(6-(4-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 170

++++ 3-(6-(4-(1-((1-methylcyclobutyl)methyl)piperidin-4-yl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 171

++++4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)phenoxy)piperidin-1-yl)-3-fluorobenzonitrile 172

++++4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)-3-oxopiperazin-1-yl)-3-fluorobenzonitrile 174

++++3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)thio)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 175

+++3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)sulfonyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 176

++++3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)sulfinyl)-2-oxobenzo[cd]indol-1(2H)-yl)pipcridine-2,6-dione 177

+++ 3-(6-((1-(3-(benzyloxy)cyclobutyl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 178

++++3-(2-oxo-6-((1-(1-(spiro[3.4]octan-5-yl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 179

++++3-(2-oxo-6-((1-(1-(spiro[3.4]octan-5-yl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)pipcridinc-2,6-dione 180

++++3-(6-((3-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 181

++++ 3-(6-((3-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-2-oxoimidazolidin-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione182

6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzo[cd]indol-2(1H)-one 183

++++4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile 184

++++4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile 185

++++4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile 186

++++3-(6-((1-(3,3-difluoro-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione187

++++3-(6-((1-(3,3-difluoro-1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione188

++++ 3-(6-(4-((4-(2-fluorophenyl)pipcrazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 189

++++ 3-(6-(4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 190

+++ 3-(6-(4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 191

++++3-(6-((1-(1-((1-methylcyclobutyl)methyl)-4-(trifluoromethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione192

++++3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione193

++++4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-1-((1-methylcyclobutyl)methyl)piperidine-4-carbonitrile 194

+++ 3-(6-((1-(4-(aminomethyl)-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione hydrochloride 195

++++ 3-(6-((1-(4-(hydroxymethyl)-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 196

++++4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)benzoyl)piperazin-1-yl)-3-fluorobenzonitrile 197

++++ 3-(2-oxo-6-(4-((3-oxomorpholino)methyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 198

++++ 3-(6-((1-(1-methylcyclohexyl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 199

++++1-((4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclopropane-1-carbonitrile200

++++3-(6-((3-chloro-1-(1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione201

++++3-(6-((3-chloro-1-(1-((1-(trif1uoromethyl)cyclopropyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 202

++++3-(6-(4-((4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 203

++++ 3-(6-(4-((1-(4-fluorophenyl)piperidin-4-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 204

3-(6-((1-(1-(1-((dimethylamino)methyl)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione205

++++3-(6-((1-(1-(1-(hydroxymethyl)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione206

++++3-(6-((3-chloro-1-(1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione207

+++3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)oxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 208

++++4-(4-((1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile209

+++4-(4-((1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-5-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile210

++++3-(2-oxo-6-(4-((4-phenylpiperazin-1-yl)methyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 211

++++3-(6-((1-(4-methyl-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 212

++++3-(6-((1-((1r,4r)-4-(tert-butoxy)cyclohexyl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 213

++++3-(6-((1-((1s,4s)-4-(tert-butoxy)cyclohexyl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 214

++++4-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobcnzo[cd]indol-6-yl)methyl)-2-fluorobenzyl)piperazin-1-yl)-3-fluorobenzonitrile 215

++++ 3-(6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 216

++++ 3-(6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 217

++++ 3-(6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 218

++++ 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 219

++++ 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidinc-2,6-dione 220

++++ 3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 221

++++3-(6-(4-(morpholinomethyl)benzyl)-2-oxopyrrolo[4,3,2-ij]isoquinolin-1(2H)-yl)piperidine-2,6-dione 222

++++ 3-(6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-2-oxopyrrolo[4.3.2-ij]isoquinolin-1(2H)-yl)piperidine-2,6-dione 223

++++3-(6-((1-(1-([1,1′-bi(cyclopropan)]-1-yl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)yl)piperidine-2,6-dione 224

++++3-(6-(4-((3-azaspiro[5.5]undecan-3-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 225

++++3-(6-(4-((8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 226

++++ 3-(6-(4-((3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 227

++++3-(2-oxo-6-(4-((4-phenylpiperidin-1-yl)methyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 228

++++ 3-(6-(4-((1-oxa-9-azaspiro[5.5]undecan-9-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 229

++++3-(6-(4-((methyl(phenyl)amino)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 230

++++ 3-(6-(4-((2-oxa-6-azaspiro[3.3)heptan-6-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 231

++++ 3-(6-(4-(((2R,6S)-2,6-dimethylmorpholino)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 232

++++ 3-(6-(4-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 233

++++3-(6-((1-(4-methyl-1-((1-methylcyclobutyl)sulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione234

++++3-(6-((1-(1-((1-methylcyclopropyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 235

++++3-(6-((1-(1-((1-methylcyclopropyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 236

++++3-(6-((1-(1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 237

++++3-(6-((1-(1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 238

++++3-(6-((1-(1-(2-oxabicyclo[2.1.1]hexane-4-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione239

++++3-(6-((1-(1-(2-oxabicyclo[2.1.1]hexane-4-carbonyl)-4-methylpiperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione240

++++3-(2-oxo-6-((1-(1-(2,2,3,3-tetramethylcyclopropyl)piperidin-4-yl)-lH-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 241

+++ tert-butyl 4-(4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbonyl)-1H-pyrazol-1-yl)-4-methylpiperidine-1-carboxylate 242

++++3-(2-oxo-6-((1-(1-(spiro[3.4]octan-5-yl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 243

++++3-(2-oxo-6-((1-(1-(spiro[3.4]octan-5-yl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 244

++++3-(2-oxo-6-((1-(1-(spiro[3.3]heptan-1-yl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 245

++++3-(2-oxo-6-((1-(1-(spiro[3.3]heptan-1-yl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 246

++++3-(6-((4-(4-(1-methylcyclobutane-1-carbonyl)piperazin-1-yl)-1H-pyrazol-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 247

++++3-(6-(methoxy(1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione248

+++ tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate249

+++3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 250

+++ tert-butyl 4-(3-chloro-4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate 251

+++3-(6-((3-chloro-1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione252

+++ tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)(methyl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate 253

++++ 3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 254

++++3-(6-(4-((4-(4-chloro-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 255

++++3-(6-(4-((4-(4-chloro-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 256

++++ 3-(6-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 257

++++ 3-(6-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 258

++++ 3-(6-(4-((4-(4-fluorophenoxy)piperidin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 259

++++ 3-(6-((1-((1s,4s)-4-neopentylcyclohexyl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 260

++++ 3-(6-((1-((1r,4r)-4-neopentylcyclohexyl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 261

++++ N-cyclopropyl-4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-N-methylpiperidine-1-carboxamide262

++++4-(4-(1-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)phenyl)cyclopropyl)piperazin-1-yl)-3-fluorobenzonitrile 263

++++ 3-(6-(4-(1-(4-(1-methylcyclobutane-1-carbonyl)piperazin-1-yl)cyclopropyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione264

++++ 3-(6-(4-(1-(4-(2-fluorophenyl)piperazin-1-yl)cyclopropyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 265

++++3-(6-((1-(1-(3-methyl-3-azabicyclo[3.1.1]heptane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione266

++++ tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)(hydroxy)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 267

++++ 3-(6-(4-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)benzyl)-2-oxopyrrolo[2,3,4-de]isoquinolin-1(2H)-yl)piperidine-2,6-dione 268

++++3-(6-((6-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)pyridin-3-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 269

++++3-(6-((6-(morpholinomethyl)pyridin-3-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 270

++++3-(6-((4-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-1-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 271

++++ 3-(6-((1-(4-methyl-1-(4-methyl-1-(pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 272

++++3-(6-((1-(4-methyl-1-(1-(pyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione273

+++ 3-(6-(4-(morpliolinomethyl)phenoxy)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 274

++++3-(6-((1-((7R)-4-(2-methylbutyl)-4-azaspiro[2.5]octan-7-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 275

++++3-(6-((1-(4-((1-methylcyclobutyl)methyl)-4-azaspiro[2.5]ocian-7-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione276

+ tert-butyl4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperidine-1-carboxylate 277

++++ 3-(6-benzyl-2-oxobenzo[cd]indol-1(2H)-yl)piperidine- 2,6-dione 278

++++3-(6-(3-fluoro-4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 279

++++4-(4-((5-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)pyridin-2-yl)methyl)piperazin-1-yl)-3-fluorobenzonitrile 280

++++3-(6-((1-(1-(1-cyclobutylethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 281

++++3-(6-((1-(1-(1-cyclobutylethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 282

++++3-(6-((1-(1-(1-cyclopropylethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 283

++++3-(6-((1-(1-(1-cyclopropylethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 284

++++ 3-(6-(4-(1-(4-(2-fluorophenyl)piperazin-1-yl)ethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 285

++++ 3-(6-(4-(1-(4-(2-fluorophenyl)piperazin-1-yl)ethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 286

++++3-(6-(4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-3-methylbenzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 287

++++3-(6-((1-(1-(1-(dimethylamino)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione288

++++3-(2-oxo-6-((1-(1-(spiro[3.3]heptan-2-yl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 289

+++3-(6-((1-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxopyrrolo[4,3,2-ij]isoquinolin-1(2H)-yl)piperidine-2,6-dione290

++++3-(6-(3-(1-(1-methylcyclobutane-1-carbonyl)piperidin-4-yl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 291

3-(6-((2-(morpholinomethyl)pyrimidin-5- yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 292

++++ tert-butyl 1-(4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 293

4-(4-((1-(2,6-dioxopiperidin-3-yl)-2-oxo- 1,2-dihydrobenzo[cd]indol-6-yl)methyl)-1H-pyrazol-1-yl)-1-((1-methylcyclopropyl)methyl)piperidine-4- carbonitrile 294

+++ 1-methyl-3-(6-((1-(1-((1-methylcyclobutyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 295

3-(2-oxo-6-(4-(piperazin-1-ylmethyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione In the above table: ++++ is < 1 nM; +++ is < 100nM; ++ is < 999 nM, and + > 999 nM.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and example for the purposes of clarity ofunderstanding, it will be readily apparent to one of ordinary skill inthe art in light of the teaching of this invention that certain changesand modification may be made thereto without departing from the spiritor scope of the invention as defined in the claims.

We claim:
 1. A method of treating a human with multiple myelomacomprising administering an effective amount of a compound of Formula

or a pharmaceutically acceptable salt or composition thereof to thehuman in need thereof; wherein: R² is independently selected at eachoccurrence from the group consisting of hydrogen, alkyl, and haloalkyl;R³ is hydrogen, halogen, alkyl, haloalkyl, —OR⁸, or NR⁸R^(8′); R^(3′) ishydrogen; R⁷ is independently selected at each occurrence from the groupconsisting of hydrogen, halogen, hydroxyl, cyano, nitro, alkyl,haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl,—OR⁸, —NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)—NR⁸R^(8′), —OC(O)R⁸,—NR²—C(O)R⁸, —S(O)R⁸, —SO₂R⁸, —SO₂—OR⁸, and —SO₂—NR⁸R^(8′); R⁸ andR^(8′) are independently selected at each occurrence from the groupconsisting of hydrogen, alkyl, haloalkyl, alkenyl, and alkynyl; and eachR⁹ is independently selected from the group consisting of hydrogen andalkyl.
 2. The method of claim 1, wherein one R⁷ is hydrogen.
 3. Themethod of claim 1, wherein two R⁷s are hydrogen.
 4. The method of claim3, wherein the remaining R⁷s are independently selected at eachoccurrence from the group consisting of alkyl, halogen, and haloalkyl.5. The method of claim 1, wherein three R⁷s are hydrogen.
 6. The methodof claim 1, wherein R⁷ is independently selected at each occurrence fromthe group consisting of hydrogen, halogen, hydroxyl, alkyl, haloalkyl,alkene, alkyne, heterocycle, aryl, and heteroaryl.
 7. The method ofclaim 1, wherein R⁷ is independently selected at each occurrence fromthe group consisting of hydrogen, alkyl, halogen, and haloalkyl.
 8. Themethod of claim 1, wherein R⁷ is independently selected at eachoccurrence from the group consisting of hydrogen and halogen.
 9. Themethod of claim 1, wherein all R⁷s are hydrogen.
 10. The method of claim1, wherein R³ is hydrogen.
 11. The method of claim 10, wherein both R⁹sare hydrogen.
 12. The method of claim 10, wherein all R⁷s are hydrogen.13. The method of claim 1, wherein both R⁹s are hydrogen.
 14. The methodof claim 13, wherein all R⁷s are hydrogen.
 15. The method of claim 13,wherein R⁷ is independently selected at each occurrence from the groupconsisting of hydrogen, halogen, hydroxyl, alkyl, haloalkyl, alkene,alkyne, heterocycle, aryl, and heteroaryl.
 16. The method of claim 13,wherein R⁷ is independently selected at each occurrence from the groupconsisting of hydrogen, alkyl, halogen, and haloalkyl.
 17. The method ofclaim 13, wherein R⁷ is independently selected at each occurrence fromthe group consisting of hydrogen and halogen.
 18. The method of claim13, wherein three R⁷s are hydrogen.
 19. The method of claim 1, whereinthe compound is

or a pharmaceutically acceptable salt thereof.
 20. The method of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 21. The method of claim20, wherein the compound is administered systematically.
 22. The methodof claim 20, wherein the compound is administered orally.
 23. The methodof claim 20, wherein the compound is administered parenterally.
 24. Themethod of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 25. The method of claim1, wherein the compound is administered systematically.
 26. The methodof claim 1, wherein the compound is administered orally.
 27. The methodof claim 1, wherein the compound is administered parenterally.